SOLUSYKLI: oktober 2018

onsdag 17 oktober 2018

EBOV VP35 inhiboi myös MDA5 sensorin.

https://www.nature.com/articles/nrmicro.2016.45/figures/3
2014 Nov;88(21):12500-10. doi: 10.1128/JVI.02163-14. Epub 2014 Aug 20.

Molecular basis for ebolavirus VP35 suppression of human dendritic cell maturation.

Yen B¹, Mulder LC², Martinez O³, Basler CF⁴.Abstract

Zaire ebolavirus (EBOV) VP35 is a double-stranded RNA (dsRNA)-binding protein that inhibits RIG-I signaling and alpha/beta interferon (IFN-α/β) responses by both dsRNA-binding-dependent and -independent mechanisms. VP35 also suppresses dendritic cell (DC) maturation. Here, we define the pathways and mechanisms through which VP35 impairs DC maturation. Wild-type VP35 (VP35-WT) and two well-characterized VP35 mutants (F239A and R322A) that independently ablate dsRNA binding and RIG-I inhibition were delivered to primary human monocyte-derived DCs (MDDCs) using a lentivirus-based expression system. VP35-WT suppressed not only IFN-α/β but also proinflammatory responses following stimulation of MDDCs with activators of RIG-I-like receptor (RLR) signaling, including RIG-I activators such as Sendai virus (SeV) or 5'-triphosphate RNA, or MDA5 activators such as encephalomyocarditis virus (EMCV) or poly(I · C). The F239A and R322A mutants exhibited greatly reduced suppression of IFN-α/β and proinflammatory cytokine production following treatment of DCs with RLR agonists. VP35-WT also blocked the upregulation of DC maturation markers and the stimulation of allogeneic T cell responses upon SeV infection, whereas the mutants did not. In contrast to the RLR activators, VP35-WT and the VP35 mutants impaired IFN-β production induced by Toll-like receptor 3 (TLR3) or TLR4 agonists but failed to inhibit proinflammatory cytokine production induced by TLR2, TLR3, or TLR4 agonists. Furthermore, VP35 did not prevent lipopolysaccharide (LPS)-induced upregulation of surface markers of MDDC maturation and did not prevent LPS-triggered allogeneic T cell stimulation. Therefore, VP35 is a general antagonist of DC responses to RLR activation. However, TLR agonists can circumvent many of the inhibitory effects of VP35. Therefore, it may be possible to counteract EBOV immune evasion by using treatments that bypass the VP35-imposed block to DC maturation. IMPORTANCE:

The VP35 protein, which is an inhibitor of RIG-I signaling and alpha/beta interferon (IFN-α/β) responses, has been implicated as an EBOV-encoded factor that contributes to suppression of dendritic cell (DC) function. We used wild-type VP35 and previously characterized VP35 mutants to clarify VP35-DC interactions. Our data demonstrate that VP35 is a general inhibitor of RIG-I-like receptor (RLR) signaling that blocks not only RIG-I- but also MDA5-mediated induction of IFN-α/β responses. Furthermore, in DCs, VP35 also impairs the RLR-mediated induction of proinflammatory cytokine production, upregulation of costimulatory markers, and activation of T cells. These inhibitory activities require VP35 dsRNA-binding activity, an activity previously correlated to VP35 RIG-I inhibitory function. In contrast, while VP35 can inhibit IFN-α/β production induced by TLR3 or TLR4 agonists, this occurs in a dsRNA-independent fashion, and VP35 does not inhibit TLR-mediated expression of proinflammatory cytokines. These data suggest strategies to overcome VP35 inhibition of DC function.Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Mikä proteiini on MDA5?

Geeni IFIH1 (2q24.2)
https://www.ncbi.nlm.nih.gov/gene/64135

AGS7; Hlcd; MDA5; MDA-5; RLR-2; IDDM19; SGMRT1

Summary

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein that is upregulated in response to treatment with beta-interferon and a protein kinase C-activating compound, mezerein. Irreversible reprogramming of melanomas can be achieved by treatment with both these agents; treatment with either agent alone only achieves reversible differentiation. Genetic variation in this gene is associated with diabetes mellitus insulin-dependent type 19. [provided by RefSeq, Jul 2012]

Expression

Ubiquitous expression in spleen (RPKM 10.9), appendix (RPKM 9.9) and 25 other tissues See more

Orthologs

mouse all

tisdag 16 oktober 2018

EBOV VP35 ja RIG-1:n aktivaattori PACT, (Geeni PRKRA(2q31.2) ( 2 DSRM - motiivia)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875338/

Ebolaviruksen VP35 proteiini estää PACT:in indusoiman RIG-1 aktivaation.
PACT- VP35- interaktio sensijaan vaikuttaa VP35- virusproteiinin ja viruspolymeraasin liittymistä ja sen takia vähentää viruksen RNA:n synteesiä eikä taas PACT itse vaikutu viruproteiinista VP35.

Mutual Antagonism between the Ebola Virus VP35 Protein and the RIG-I Activator PACT Determines Infection Outcome

The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection.

KUVA tästä tekstistä:

Figure 7

Working Model for Mutual Antagonism between VP35 and PACT

EBOV VP35 functions as an inhibitor of RIG-I signaling and as an essential component of the viral RNA replication complex. VP35 can block either the RNA- or the PACT-mediated activation of RIG-I, but PACT can inhibit the RNA replication complex through interaction with VP35. Under conditions in which VP35 levels may be limited, PACT interaction with VP35 may slow virus replication, resulting in decreased production of immunostimulatory viral replication products. This would allow VP35 to sense the immune status through PACT availability and thereby regulate replication accordingly.

Mikä tekijä on PACT?
PKR- aktivaattori. hiirellä vastaava on nimeltään PKR:ään liittynyt X (RAX).
Tässä propteiinissa on DRBM- motiivi. dsRNA sitova motiivi

Geeni PRKRA, (2q31.2) , synonyyminimet PACT, RAX, DYT16, HSD14.

https://www.ncbi.nlm.nih.gov/gene/8575

RAX; PACT; DYT16; HSD14

Preferred Names: interferon-inducible double-stranded RNA-dependent protein kinase activator A

Names: PKR-associated protein X; PKR-associating protein X; protein activator of the interferon-induced protein kinase; protein kinase, interferon-inducible double-stranded RNA-dependent activator

Summary

This gene encodes a protein kinase activated by double-stranded RNA which mediates the effects of interferon in response to viral infection. Mutations in this gene have been associated with dystonia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

Expression

Ubiquitous expression in testis (RPKM 15.5), endometrium (RPKM 12.4) and 25 other tissues See more

Orthologs

mouse all

Conserved Domains (2) summary

smart00358 Location:10 → 75: DSRM; Double-stranded RNA binding motif ( as in Drosophila staufen)

cd00048 Location:101 → 167: DSRM; Double-stranded RNA binding motif. Binding is not sequence specific but is highly specific for double stranded RNA. Found in a variety of proteins including dsRNA dependent protein kinase PKR, RNA helicases, Drosophila staufen protein, E. coli RNase III, and dsRNA dependent adenosine deaminases.

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

Mitokondria

http://jonlieffmd.com/blog/dynamic-relationship-of-mitochondria-and-neurons

Endoplasminen verkosto ER ja sen jäseniä:

https://alevelbiology.co.uk/notes/endoplasmic-reticulum-structure-and-function/
http://jonlieffmd.com/blog/special-relationship-viruses-endoplasmic-reticulum

Löysin yhden struktuuriproteiinin:
Geeni SEC61A1 (3q21.3) https://www.ncbi.nlm.nih.gov/gene/29927

HNFJ4; SEC61; HSEC61; SEC61A
Summary: The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. [provided by RefSeq, Jul 2008]
Expression: Ubiquitous expression in thyroid (RPKM 81.0), placenta (RPKM 70.7) and 25 other tissues See more
Orthologs: mouse all; UUSINTA TIETOA tästä Sec61 transloconista:; https://www.frontiersin.org/articles/10.3389/fphys.2017.00887/full; https://www.frontiersin.org/files/Articles/291873/fphys-08-00887-HTML/image_m/fphys-08-00887-g006.jpg

Staufen STAU1 ja Ebolavirus

Ebola virus (EBOV) genome and mRNAs contain long, structured regions that could hijack host RNA-binding proteins to facilitate infection. We performed RNA affinity chromatography coupled with mass spectrometry to identify host proteins that bind to EBOV RNAs and identified four high-confidence proviral host factors, including Staufen1 (STAU1), which specifically binds both 3′ and 5′ extracistronic regions of the EBOV genome. We confirmed that EBOV infection rate and production of infectious particles were significantly reduced in STAU1-depleted cells. STAU1 was recruited to sites of EBOV

RNA synthesis upon infection and enhanced viral RNA synthesis. Furthermore, STAU1 interacts with EBOV nucleoprotein (NP), virion protein 30 (VP30), and VP35; the latter two bridge the viral polymerase to the NP-coated genome, forming the viral ribonucleoprotein (RNP) complex.STAU1 plays a critical role in EBOV replication by coordinating interactions between the viral genome and RNA synthesis machinery.

LÄHDE: https://mbio.asm.org/content/9/5/e01771-18#sec-9

DISCUSSION

Our data provide evidence that STAU1 is the first cellular factor reported to associate with three essential components of the EBOV RNA synthesis machinery: NP, VP35, and VP30. The NP-VP35 complex serves as a critical backbone for the viral polymerase L to recognize NP-encapsidated RNA genomes, which is the prerequisite for both EBOV transcription and genome replication. Similarly, VP30 is also believed to bridge interactions between L and NP, and it is critical for transcription of viral mRNA (13, 57). Our observations further imply an association of STAU1 with the EBOV RNA genome-NP-VP35 complex, suggesting that regions of the EBOV genome are available for interaction with trans-acting factors in the presence of NP. Related to our finding that STAU1 preferentially binds to 3′ and 5′ extracistronic regions of the EBOV genome in vitro, we propose a model in which STAU1 is involved in the early formation of EBOV RNA synthesis machinery on the 3′ extracistronic region of the EBOV genome, and likewise, in the termination and release of EBOV RNA synthesis machinery on the 5′ extracistronic region (see Fig. S8 in the supplemental material).

Previous efforts have been made to understand EBOV host factor biology by focusing on protein-protein interactions between viral and host proteins (58 –62). To provide more insights into how host factors regulate EBOV replication through cis-acting elements in EBOV RNA, we performed a RAC-MS screen and discovered 14 host RBPs specifically enriched for the selected EBOV noncoding RNAs. Among these RBPs, ILF2, ILF3, HNRNPL, and STAU1 stand out as strong EBOV candidate host factors because all three siRNAs tested caused a significant reduction of EBOV infection. While HNRNPL preferentially associated with the 5′ UTR of EBOV NP mRNA, ILF2, ILF3, and STAU1 selectively interacted with the EBOV trailer. It is noteworthy that ILF3 (also known as DRBP76/NF90) was previously identified as a VP35 interactor as well as an EBOV polymerase suppressor (61). Although this previous study did not observe a dramatic effect of reduced ILF3 expression on EBOV infection in 293T cells, the data we present here showed that depletion of ILF3 in HuH-7 cells significantly impaired EBOV infection. This discrepancy could be explained by cell line differences. Nevertheless, the identification of ILF2 (or NF45) in our screen, which is physically and functionally linked to ILF3 (44), highlights the important role that ILF3 perhaps has in EBOV infection.

We focused on STAU1 as a novel EBOV host factor that promotes efficient virus infection. STAU1 is a protein that binds to stable RNA secondary structure (63), a tubulin-binding protein that interacts with cytoskeleton (50), a ribosome-associated protein (64, 65) that accumulates in stress granules induced by certain types of stress (66), and a key mediator of mRNA decay (67, 68). These biochemical characteristics enable STAU1 to fulfill different biological functions: from controlling the localization to enhancing the translation of its target RNAs. Therefore, elucidation of a functional domain(s) of STAU1 that is responsible for EBOV host factor activity may allow generation of targeted inhibitors antagonizing the STAU1 proviral effect.

Previous studies of several RNA viruses have revealed that STAU1 binding to viral RNA regulates infection. For instance, STAU1 facilitates translation of hepatitis C virus RNA through binding to the internal ribosome entry site (46). STAU1 plays a role in the production of viral particles for both influenza A virus (47) and human immunodeficiency virus type 1 (48). Our RAC-MS results indicated that STAU1 preferentially associates with EBOV genomic RNA and not with the 5′ UTR of two viral mRNAs. Therefore, it is unlikely that STAU1 promotes EBOV mRNA translation; however, we tested only the 5′ UTRs of NP and VP24 transcripts, so we cannot eliminate the possibility that STAU1 may bind to other UTRs and participate in their translation. Another caveat is that the EBOV genomic RNA used in the RAC experiment was naked, while during infection, it is likely to be mostly encapsidated by NP and therefore relatively inaccessible (). Nevertheless, the facts that STAU1 is recruited to sites of viral RNA synthesis and forms a complex in cells with NP, VP35, and minigenome RNA suggest interactions between STAU1 and EBOV genomic RNA in infected cells.

Several other stress granule (SG) markers (for instance, the initiation factors eIF3 and eIF4G) were previously found to localize on discrete, compact granules within EBOV inclusion bodies (30). In contrast to this, STAU1 in EBOV inclusion bodies appeared in a heterogeneous pattern that changed over the course of infection. In some areas near the border of EBOV inclusion bodies, where VP35 was almost absent, STAU1 formed small aggregates that branched out of the inclusion border (Fig. S5C). This distinct distribution of STAU1 suggests that it may function differently than other SG proteins with regard to interactions with EBOV inclusion bodies.

Given the correlation between the level of STAU1 expression and EBOV minigenome activity, it is of interest to pinpoint the molecular event(s) STAU1 regulates during EBOV RNA synthesis. For nonsegmented, negative-sense RNA viruses, the first step of viral RNA synthesis is primary transcription in order to generate sufficient levels of viral proteins. When a supply of NP has been synthesized, genome replication and secondary transcription are allowed to commence, leading to the production of encapsidated antigenomes and progeny genomes as well as naked mRNAs (70). Attempts to distinguish whether STAU1 enhances genome replication or transcription using the minigenome system by strand-specific quantitative PCR (qPCR) were not successful, however, due to residual DNA from transfected plasmids despite DNase treatment of RNA samples. Future studies using other model systems (i.e., replication-deficient minigenome) are required to ascertain whether STAU1 participates in EBOV transcription (71).

Preliminary characterization of STAU1-associated EBOV minigenome RNP (reconstituted by EBOV minigenome RNA, NP, and VP35) revealed another interesting cellular player, PKR. Although PKR is well-known for its antiviral function by sensing viral RNA and phosphorylating the host translation initiation factor eIF2α (72), it has also been implicated in the phosphorylation and regulation of the HIV trans-acting protein Tat, which binds to the transactivation-responsive element (TAR) in the HIV genome, in the context of viral infection (73, 74). Interestingly, no host kinase has yet been reported to regulate phosphorylation of EBOV VP30, even though a growing number of studies indicate a crucial role of dynamic VP30 phosphorylation in EBOV RNA synthesis and RNP assembly (19, 21, 55, 75, 76). Although several reports indicate that EBOV antagonizes PKR activity (53, 54), one can imagine scenarios in which PKR is hijacked by this STAU1-containing viral RNP complex to dynamically control the phosphorylation of EBOV VP30. Further investigation is needed to clarify the role of PKR in EBOV infection.

In conclusion, we identified STAU1 as the first host factor reported to interact with multiple EBOV RNP components, highlighting the significance of this RBP for the EBOV life cycle. These interactions together with redistribution of STAU1 to EBOV inclusion bodies and to NP-induced inclusion bodies link STAU1 to EBOV RNA synthesis, for which we speculate that STAU1 facilitates both the initiation and termination steps. It will be of interest to clarify the exact molecular events occurring during initiation and termination of EBOV RNA synthesis and how STAU1 may participate in these processes. Our study contributes to knowledge of the role of host factors in EBOV RNA synthesis and provides a novel cellular target for the development of possible therapeutic interventions to combat EBOV infection.

STAU1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156307/Abstract

Staufen (Stau) proteins belong to a family of RNA-binding proteins (RBPs) that are important for RNA localisation in many organisms. In this review we discuss recent findings on the conserved role played by Stau during both the early differentiation of neurons and in the synaptic plasticity of mature neurons. Recent molecular data suggest mechanisms for how Stau2 regulates mRNA localisation, mRNA stability, translation, and ribonucleoprotein (RNP) assembly. We offer a perspective on how this multifunctional RBP has been adopted to regulate mRNA localisation under several different cellular and developmental conditions.

Keywords: RNA localisation, Staufen, neurogenesis, synaptic plasticity, RNP, mRNA stability, learning and memory

dsRNA:ta sitova ihmisen soluproteiini Staufen

Otan yhden staufen-proteiinin peptidirakenteen tähän esimerkiksi. isoformi a.
Tälle proteiinille on tyypillsitä useampi DSRM- motiivi ( dsRNA:ta sitova motiivi) .
Vuonna 1996 on julkaistu artikkeli tätä proteiinia koodaavan geenin sijoittumisesta kromosomiin 20q13.3. Geenin nimi STAU. ( Jo Drosophilass on staufin- geeni).
Vuonna 1999 tiedetään, että Ihmesen staufen-sekvenssi on RNA:ta sitova proteiini, ja se assosioituu polysomeihin ja sijoittautuu karkeaan endoplasmiseen retikulumiin (RER). Samana vuonna havaitaan että imettäväisillä staufen liittuu tubuliiniin. Ihmisellä staufen tekee interaktion influenssaviruksen NS1-proteiinin kanssa koeputkessa ja in vivo.
Vuonna 2000 on saatu oivalluksia mRNA-kuljetuksesta ja paikallisesta translaatiosta imettäväisten hermojärjestelmässä.
On huomattu, että SNHG5 stabiloi kohdetranskriptejä blokeeraamalla niiden hajoittamisen STAU1:llä . Sen mukaan STAU1- depleetio palauttaa apoptoosin, jonka on indusoinut SNHG5 poistogeenisyys. Täten SNHG5 luonnehditaan lncRNA:ksi, joka edisiää tuumorisolun elossapysymistä kolorektaalisyövässä.
Vuonna 2016 artikkeli: SNHG5 edistää kolorektaalisyöpäsolun elossapysymistä vastavaikuttamalla STAU-1 välitteiseen mRNA:n destabilisoimiseen.
Vuonna 2017: Influenssaproteiini-interaktomeista tunnistetaan plakofiliini 2:n osuus virusrestriktiossa . Samana vuonna todetaan , että ADAR1 kontrolloi stressattujen solujen apoptoosia estämällä Staufen1- välitteisen mRNA- hajoituksen ( ADAR1p110 isoformi estää kompetitiivisesti Staufen1:n sitoutumisen dsRNA:n 3´UTR-alueeseen ja vastavaikuttaa Staufen1- välitteiseen mRNA:n hävittämiseen).
E2F1 indusoi TINCR transkriptaalisen aktiivisuuden ja kiihdyttää mahasyövän progredioitumista aktivoimalla TINCR/STAU1/CDKN2B-signalointiakselin.
lncRNA Chronos on ikääntymisen indusoima lihashypertrofian estäjä

Sitaatti  STAU1 isoformi a rakenteesta:

double-stranded RNA-binding protein Staufen homolog 1 isoform a [Homo sapiens]

NCBI Reference Sequence: NP_004593.2

Identical Proteins FASTA Graphics

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LOCUS       NP_004593                496 aa            linear   PRI 24-SEP-2018
DEFINITION  double-stranded RNA-binding protein Staufen homolog 1 isoform a
            [Homo sapiens].
ACCESSION   NP_004593
VERSION     NP_004593.2
DBSOURCE    REFSEQ: accession NM_004602.3
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 496)
  AUTHORS   Neppl RL, Wu CL and Walsh K.
  TITLE     lncRNA Chronos is an aging-induced inhibitor of muscle hypertrophy
  JOURNAL   J. Cell Biol. 216 (11), 3497-3507 (2017)
   PUBMED   28855249
REFERENCE   2  (residues 1 to 496)
  AUTHORS   Xu TP, Wang YF, Xiong WL, Ma P, Wang WY, Chen WM, Huang MD, Xia R,
            Wang R, Zhang EB, Liu YW, De W and Shu YQ.
  TITLE     E2F1 induces TINCR transcriptional activity and accelerates gastric
            cancer progression via activation of TINCR/STAU1/CDKN2B signaling
            axis
  JOURNAL   Cell Death Dis 8 (6), e2837 (2017)
   PUBMED   28569791
  REMARK    GeneRIF: E2F1 induces TINCR transcriptional activity and
            accelerates gastric cancer progression via activation of
            TINCR/STAU1/CDKN2B signaling axis.
            Publication Status: Online-Only
REFERENCE   3  (residues 1 to 496)
  AUTHORS   Sakurai M, Shiromoto Y, Ota H, Song C, Kossenkov AV, Wickramasinghe
            J, Showe LC, Skordalakes E, Tang HY, Speicher DW and Nishikura K.
  TITLE     ADAR1 controls apoptosis of stressed cells by inhibiting
            Staufen1-mediated mRNA decay
  JOURNAL   Nat. Struct. Mol. Biol. 24 (6), 534-543 (2017)
   PUBMED   28436945
  REMARK    GeneRIF: ADAR1p110 isoform competitively inhibits binding of
            Staufen1 to the 3'-untranslated-region dsRNAs and antagonizes
            Staufen1-mediated mRNA decay.
REFERENCE   4  (residues 1 to 496)
  AUTHORS   Wang L, Fu B, Li W, Patil G, Liu L, Dorf ME and Li S.
  TITLE     Comparative influenza protein interactomes identify the role of
            plakophilin 2 in virus restriction
  JOURNAL   Nat Commun 8, 13876 (2017)
   PUBMED   28169297
  REMARK    Publication Status: Online-Only
REFERENCE   5  (residues 1 to 496)
  AUTHORS   Damas ND, Marcatti M, Come C, Christensen LL, Nielsen MM,
            Baumgartner R, Gylling HM, Maglieri G, Rundsten CF, Seemann SE,
            Rapin N, Thezenas S, Vang S, Orntoft T, Andersen CL, Pedersen JS
            and Lund AH.
  TITLE     SNHG5 promotes colorectal cancer cell survival by counteracting
            STAU1-mediated mRNA destabilization
  JOURNAL   Nat Commun 7, 13875 (2016)
   PUBMED   28004750
  REMARK    GeneRIF: Mechanistically, we suggest that SNHG5 stabilizes the
            target transcripts by blocking their degradation by STAU1.
            Accordingly, depletion of STAU1 rescues the apoptosis induced after
            SNHG5 knockdown. Hence, we characterize SNHG5 as a lncRNA promoting
            tumour cell survival in colorectal cancer.
            Publication Status: Online-Only
REFERENCE   6  (residues 1 to 496)
  AUTHORS   Kiebler MA and DesGroseillers L.
  TITLE     Molecular insights into mRNA transport and local translation in the
            mammalian nervous system
  JOURNAL   Neuron 25 (1), 19-28 (2000)
   PUBMED   10707969
  REMARK    Review article
REFERENCE   7  (residues 1 to 496)
  AUTHORS   Falcon AM, Fortes P, Marion RM, Beloso A and Ortin J.
  TITLE     Interaction of influenza virus NS1 protein and the human homologue
            of Staufen in vivo and in vitro
  JOURNAL   Nucleic Acids Res. 27 (11), 2241-2247 (1999)
   PUBMED   10325410
REFERENCE   8  (residues 1 to 496)
  AUTHORS   Wickham L, Duchaine T, Luo M, Nabi IR and DesGroseillers L.
  TITLE     Mammalian staufen is a double-stranded-RNA- and tubulin-binding
            protein which localizes to the rough endoplasmic reticulum
  JOURNAL   Mol. Cell. Biol. 19 (3), 2220-2230 (1999)
   PUBMED   10022909
REFERENCE   9  (residues 1 to 496)
  AUTHORS   Marion RM, Fortes P, Beloso A, Dotti C and Ortin J.
  TITLE     A human sequence homologue of Staufen is an RNA-binding protein
            that is associated with polysomes and localizes to the rough
            endoplasmic reticulum
  JOURNAL   Mol. Cell. Biol. 19 (3), 2212-2219 (1999)
   PUBMED   10022908
REFERENCE   10 (residues 1 to 496)
  AUTHORS   DesGroseillers L and Lemieux N.
  TITLE     Localization of a human double-stranded RNA-binding protein gene
            (STAU) to band 20q13.1 by fluorescence in situ hybridization
  JOURNAL   Genomics 36 (3), 527-529 (1996)
   PUBMED   8884277
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from DB100321.1, BC095397.1,
            BC001893.1, BC050432.1, AF061941.1, AK091405.1 and BE439382.1.
            On Nov 25, 2005 this sequence version replaced NP_004593.1.

  Summary: Staufen is a member of the family of double-stranded RNA
            (dsRNA)-binding proteins involved in the transport and/or
            localization of mRNAs to different subcellular compartments and/or
            organelles. These proteins are characterized by the presence of
            multiple dsRNA-binding domains which are required to bind RNAs
            having double-stranded secondary structures. The human homologue of
            staufen encoded by STAU, in addition contains a microtubule-
            binding domain similar to that of microtubule-associated protein
            1B, and binds tubulin. The STAU gene product has been shown to be
            present in the cytoplasm in association with the rough endoplasmic
            reticulum (RER), implicating this protein in the transport of mRNA
            via the microtubule network to the RER, the site of translation.
            Five transcript variants resulting from alternative splicing of
            STAU gene and encoding three isoforms have been described. Three of
            these variants encode the same isoform, however, differ in their
            5'UTR. [provided by RefSeq, Jul 2008].
            
            Transcript Variant: This variant (T4) has an additional exon in the
            5' UTR compared to T2, the most abundantly expressed transcript
            variant. T4 encodes the same isoform (a) of 496 amino acids as T2.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: SRR1803615.3249.1,
                                           SRR1803613.62205.1 [ECO:0000332]
            RNAseq introns              :: mixed/partial sample support
                                           SAMEA1965299, SAMEA1966682
                                           [ECO:0000350]
            ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..496
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="20"
                     /map="20q13.13"
     Protein         1..496
                     /product="double-stranded RNA-binding protein Staufen
                     homolog 1 isoform a"
                     /note="staufen, RNA binding protein, homolog 1; protein
                     phosphatase 1, regulatory subunit 150"
                     /calculated_mol_wt=54803
     Region          105..169
                     /region_name="DSRM"
                     /note="Double-stranded RNA binding motif; smart00358"
                     /db_xref="CDD:214634"
     Site            order(109..110,151..154,157)
                     /site_type="other"
                     /note="dsRNA binding site [nucleotide binding]"
                     /db_xref="CDD:238007"
     Region          205..271
                     /region_name="DSRM"
                     /note="Double-stranded RNA binding motif. Binding is not
                     sequence specific but is highly specific for double
                     stranded RNA. Found in a variety of proteins including
                     dsRNA dependent protein kinase PKR, RNA helicases,
                     Drosophila staufen protein, E. coli RNase III; cd00048"
                     /db_xref="CDD:238007"
     Site            order(205,211..212,254..257,260)
                     /site_type="other"
                     /note="dsRNA binding site [nucleotide binding]"
                     /db_xref="CDD:238007"
     Region          367..476
                     /region_name="Staufen_C"
                     /note="Staufen C-terminal domain; pfam16482"
                     /db_xref="CDD:318642"
     CDS             1..496
                     /gene="STAU1"
                     /gene_synonym="PPP1R150; STAU"
                     /coded_by="NM_004602.3:492..1982"
                     /note="isoform a is encoded by transcript variant T4"
                     /db_xref="CCDS:CCDS13415.1"
                     /db_xref="GeneID:6780"
                     /db_xref="HGNC:HGNC:11370"
                     /db_xref="MIM:601716"
ORIGIN      
        1 mklgkkpmyk pvdpysrmqs tynynmrgga yppryfypfp vppllyqvel svggqqfngk
       61 gktrqaakhd aaakalrilq neplperlev ngreseeenl nkseisqvfe ialkrnlpvn
      121 fevaresgpp hmknfvtkvs vgefvgegeg kskkiskkna aiavleelkk lpplpaverv
      181 kprikkktkp ivkpqtspey gqginpisrl aqiqqakkek epeytllter glprrrefvm
      241 qvkvgnhtae gtgtnkkvak rnaaenmlei lgfkvpqaqp tkpalkseek tpikkpgdgr
      301 kvtffepgsg dengtsnked efrmpylshq qlpagilpmv pevaqavgvs qghhtkdftr
      361 aapnpakatv tamiarelly ggtsptaeti lknnissghv phgpltrpse qldylsrvqg
      421 fqveykdfpk nnknefvsli ncssqpplis hgigkdvesc hdmaalnilk llseldqqst
      481 emprtgngpm svcgrc
//

söndag 14 oktober 2018

NOD-kaltainen reseptori NLRB, NAIP3 (5q13.2)

https://www.ncbi.nlm.nih.gov/gene

NAIP3 geenin vaihtoehtoisia nimiä ovat BIRC1, NLDB1, psiNAIP.

(Suomennosta) Suositellut nimet: Bakuloviraali IAP toiston sisältävä proteiini1
Nimet: Neuronaalinen apoptoosia estävä proteiini (NAIP)
Nukleotidiä sitovan oligomerisaatiodomeenin (NOD), leusiinipitoinen toiston (LRR) ja BIR-domeenin sisältävä 1 psi neuronaalinen apoptoosia estävä proteiini (NAIP)

Preferred Names

baculoviral IAP repeat-containing protein 1

Names

neuronal apoptosis inhibitory protein

nucleotide-binding oligomerization domain, leucine rich repeat and BIR domain containing 1

psi neuronal apoptosis inhibitory protein

(Suomennosta) NOD:n kaltainen reseptori NLRB on NAIP.
Sen geeni NAIP3 on 500 kb:n osa invertoituneesta duplikaatiosta kromosomissa 5q13.2. Tämä kaksinkertaistunut alue sisältää ainakin neljä geeniä ja toistoelementtejä, mikä altistaa sitä uudelleenjärjestymisille ja deleetioille. Sekvenssin toistotaipumus ja monimutkaisuus on tuottanut vaikeuksia määrittää sen genomisen alueen organisoituminen. Tämä geenikopio on kokopitkä (NAIPFull). On myös olemassa tästä geenialueesta 5q13 lisäkopioita lyhentyneine muotoineen (truncated) ja sisäisine deleetioineen. In ajateltu, että tämä geeni olisi spinaalisen lihasatrofian modifioija- tätä lihastautia aiheuttaa naapurigeenin SMN1:n mutaatiot.
Tämän geenin koodaama proteiini sisältää homologisia alueita bakuloviruksen kahdelle apoptoosiproteiini -inhibiittorille ja se kykenee vaimentamaan erilaisten signaalien indusoimaa apoptoosia. Vaihtoehtoispleissauksesta ja vaihtoehtoisista promoottoreista seuraa monia transkriptivariantteja. Tätä geeniä ilmenee umpilisäkkeessä, pernassa ja 23 muussa kudoksessa.

BIRC1; NLRB1; psiNAIP Summary This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. This copy of the gene is full length; additional copies with truncations and internal deletions are also present in this region of chromosome 5q13. It is thought that this gene is a modifier of spinal muscular atrophy caused by mutations in a neighboring gene, SMN1. The protein encoded by this gene contains regions of homology to two baculovirus inhibitor of apoptosis proteins, and it is able to suppress apoptosis induced by various signals. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Nov 2016]Expression
Broad expression in appendix (RPKM 20.5), spleen (RPKM 11.7) and 23 other tissues See moreOrthologs

NOD:in kaltaisen reseptorin signaalitie, hyvä kartta

https://www.ncbi.nlm.nih.gov/biosystems/122191?Sel=geneid:4671#show=genes

NOD-like receptor signaling pathway

Specific families of pattern recognition receptors (PRR) are responsible for detecting various pathogens and generating innate immune responses.

The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands.

NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis.

On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes.

The activated of caspase-1 regulates maturation of the pro-inflammatory cytokines IL-1B, IL-18 and drives pyroptosis.

from KEGG source record: hsa04621
Type: pathway (human)

https://www.kegg.jp/pathway/hsa04621

Lektiinit, Lektiiniryhmät

Kertausta LEKTIINEISTÄ, varsinkin animaalissita lektiineistä.
lektiineitä on kaikkialla luonnossa, muta tässä koetan selvittää niistä sellaisia, jotka ovat ihmiselle tärkeitä ihmisen ja ympräistän rajapinnassa, esim ihmisenimmuunijärjestelmän kyvssä tunnistaa mikrobeita hahmontunnsitusjärjestelmällä.
http://www.imperial.ac.uk/research/animallectins/ctld/lectins.html http://www.imperial.ac.uk/research/animallectins/ctld/lectins.html

Johdantoa lektiiniperheisiin.
Tämä netistä löytynyt artikkeli antaa yhteenvedon tunnetuista lektiiniperheistä ja yleiskatsauksen niiden soluun sijoittautumisesta, ligandia sitovista ominaisuuksista ja eri perheitten evoluutiosta .Lisäksi on mainittu linkkejä, joista saa yksityiskohtaista tietoa jokaisen lektiiniperheen rakenteesta, sokeria sitovasta aktiivisuudesta, biologisesta funktiosta ja perheeseen kuuluvien proteiinien evoluutiosta ja sekvensseistä.
Solupinnoilla monimutkaiset oligosakakridirakenteet ovat petautuneena extrasellulaariseen matriisiin (ECM) ja liittyneenä eritettyihin glykoproteiineihin (gp). Näillä oligosakkarideilla voi olla rakenteellisia tehtäviä, ne voivat välittää glykokonjugaattien liikettä solupintaan tai ne toimivat markkereina, jotka välittävät solu-solu- tai solu- matriisi-tunnistustapahtumia. Sokereitten struktuurittomat roolit yleensä vaativat sokeria sitovien lektiinien osallistumista, ja niissä sokeria sitova aktiivisuus perustuu johonkin lektiinipolypeptisissä olevaan yksittäiseen proteiinimoduliin tässä lektiinipolypeptidissä. (Lektiinipolypeptidit sisältävät typpeä ja sen takia lektiineillä on selkeät hahmonsa, struktuurit, jonka suhteen sokerit ovat struktuurittomia- esim sokerista ei voi rakentaa kehokudoksia, ne ovat energia-aine; sokerit tarvitsevat lektiiniapua). Lektiinien moduleita merkataan CRD, hiilihydraattia tunnistava domeeni.

Introduction to lectin families

This page provides a summary of the known lectin families, and an overview of the subcellular location and ligand binding specificities and evolution of the different families. The links below provide more detailed information on the structure, sugar-binding activity, biological function and evolution of proteins in each of the lectin families as well as annotated sequence alignments.

Complex oligosaccharide structures are displayed at cell surfaces, incorporated into the extracellular matrix and attached to secreted glycoproteins. These oligosaccharides can serve structural roles, mediate movement of glycoconjugates to the cell surface or act as markers that mediate cell-cell and cell-matrix recognition events. The non-structural roles of sugars generally require the participation of sugar-binding lectins (Drickamer and Taylor, 1998), in which sugar-binding activity can usually be ascribed to a single protein module within the lectin polypeptide. Such a module is referred to a carbohydrate-recognition domain (CRD).

Selkärankaisten CRD- moduleita omaavissa lektiineissa on havaittu lukuisia rakenteellisesti erilaisia perheitä. Kahdeksan hyvin selvitettyä ryhmää jaetaan neljän lektiiniperheen ryhmään, jotka lähinnä esiintyvät solunsisäisesti eli intrasellulaarisesti ja toiseen neljään ryhmään, jotka esiintyvät extrasellulaarisesti.

Intrasellulaariet lektiiniperheet ovat :

1. Calnexiiniperhe

2. M-tyyppisen lektiinin perhe

3. L-tyyppisen lektiinin perhe

4. P-tyyppisen lektiinin perhe.

(Nämä sijaitsevat solun luminaalisissa aitioissa, kalvojen muodostamissa onteloissa, sekretorisen tien alueella ja toimivat eritettävien glykoproteiinien kypsymisprosessissa liikennöinnissä, lajittelussa ja kohdentamisessa)

Extrasellulaariset lektiiniperheet ovat

5. C-tyyppisen lektiinin perhe

6. R-tyyppisen lektiinin perhe

7. Siglec- perhe

8. Galektiiniperhe

(Nämä erittyvät joko extrasellulaariseen matriisiin (ECM) tai kehonesteisiin tai niitä sijoittautuu plasmakalvoon (PM) ja ne välittävät useita funktioita, solun adheesiosta signalointiin, glykoproteiinin poispuhdistamiseen ja patogeeenin hahmontunnistukseen (PAMP tunnistus))

Uudempana löytönä pidetään animaalisten lektiinien lisäryhmää.

9. F-box-lektiinit

10. Fikoliinit

11. Kitinaasin kaltaiset lektiinit

12. F-tyyppiset lektiinit

13. Intelektiini, eglektiinit

(Näistä joillakin on edellisiä täydentäviä tehtäviä)

CRDs in vertebrate lectins fall into a number of structurally distinct families. Of the eight well-established groups, four contain lectins that are predominantly intracellular and four contain lectins that generally function outside the cell. The intracellular lectins - calnexin family, M-type, L-type and P-type - are located in luminal compartments of the secretory pathway and function in the trafficking, sorting and targeting of maturing glycoproteins. The extracellular lectins - C-type, R-type, siglecs and galectins - are either secreted into the extracellular matrix or body fluids, or localized to the plasma membrane, and mediate a range of functions including cell adhesion, cell signalling, glycoprotein clearance and pathogen recognition. Recent findings point to the existence of additional new groups of animal lectins - F-box lectins, ficolins, chitinase-like lectins, F-type lectins and intelectins - some of which have roles complementary to those of the well-established lectin families.

Artikkeliin liittyy valaiseva kuva solun kalvojärjstelmästä, joka tekee glykoproteiinien kypsyttämistä ja eritystä solupintaa kohtaan. Tämän kypsymisen aikana on tärkeä proteiinin oikea laskostuminen. Jos laskostuminen on väärää, proteiini joutuu ERAD- hajoitukseen (Endoplasmiseen retikulumiin assosioitunut hajoitustie, Unfolded protein response (UPR), Endoplasmisen retikulumin laadunkotnrollijärjestelmä (ERQC), endoplasmiseen retikulumiin assosioitunut hajoittaminen, ( ERAD).

Sections in this page
Summary of lectin families
Location and ligand binding specificity
Reference : Drickamer, K. and Taylor, M.E. (1998) Evolving views of protein glycosylation. Trends Biochem. Sci., 23, 321-324.
Evolution

Information
Calnexin M-type L-type P-type R-type Galectins I-type C-type
F-box lectins Ficolins Chitinase-like lectins F-type Intelectins

Sequence alignments
Calnexin M-type L-type P-type R-type Galectins I-type C-type
F-box lectins Ficolins Chitinase-like lectins F-type Intelectins

Summary of lectin families

Lectin family	Typical saccharide ligands	Subcellular location	Examples of functions
Calnexin	Glc₁Man₉	ER	Protein sorting in the endoplasmic reticulum.
M-type lectins	Man₈	ER	ER-associated degradation of glycoproteins.
L-type lectins	Various	ER, ERGIC, Golgi	Protein sorting in the endoplasmic reticulum.
P-type lectins	Man 6-phosphate, others	Secretory pathway	Protein sorting post-Golgi, glycoprotein trafficking, ER-associated degradation of glycoproteins, enzyme targeting.
C-type lectins	Various	Cell membrane, extracellular	Cell adhesion (selectins), glycoprotein clearance, innate immunity (collectins).
Galectins	b-Galactosides	Cytoplasm, extracellular	Glycan crosslinking in the extracellular matrix.
I-type lectins (siglecs)	Sialic acid	Cell membrane	Cell adhesion.
R-type lectins	Various	Golgi, Cell membrane	Enzyme targeting, glycoprotein hormone turnover.
F-box lectins	GlcNAc₂	Cytoplasm	Degradation of misfolded glycoproteins.
Ficolins	GlcNAc, GalNAc	Cell membrane, extracellular	Innate immunity.
Chitinase-like lectins	Chito-oligosaccharides	Extracellular	Collagen metabolism (YKL-40).
F-type lectins	Fuc-terminating oligosaccharides	Extracellular	Innate immunity.
Intelectins	Gal, galactofuranose, pentoses	Extracellular/cell membrane	Innate immunity. Fertilization and embryogenesis.

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