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.

 

Related articles in PubMed

1. PRKRA Mutation Causing Early-Onset Generalized Dystonia-Parkinsonism (DYT16) in an Italian Family. Quadri M, et al. Mov Disord, 2016 May. PMID 26990861
2. Regulation of PACT-Mediated Protein Kinase Activation by the OV20.0 Protein of Orf Virus. Tseng YY, et al. J Virol, 2015 Nov. PMID 26355092, Free PMC Article
3. DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family. Zech M, et al. Mov Disord, 2014 Oct. PMID 25142429
4. PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator. Kim Y, et al. Genes Dev, 2014 Jun 15. PMID 24939934, Free PMC Article
5. Mutational analysis of PACT gene in Chinese patients with microtia. Lin L, et al. Am J Med Genet A, 2011 Apr. PMID 21595004

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Low PACT expression is associated with Arenaviral infections.
2. phenotype of our patients overlaps that of previouslyreported DYT16 patients
3. this study shows that PACT is an essential coactivator of the MDA5-dependent type I IFN response to viral RNA
4. High PRKRA mRNA expression is associated with colorectal cancer.
5. It was established in this report that interactions between PACT, ADAR1 and HIV-1-encoded Tat protein diminish the activation of PKR in response to HIV-1 infection.
6. 5 genomic variants in GSC, HOXA2 and PRKRA were identified through mutational analysis in Chinese patients with microtia.
7. MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells.
8. The interferon-induced protein kinase(PACT) partially rescued defects of interferon-beta1 and chemokine (C-C motif) ligand 5/RANTES (regulated on activation normal T cell expressed and secreted) induction in DDX3-knockdown HEK293 cells.
9. These findings support a model in which a measles virus defective interfering RNA is sensed by PACT and RIG-I to initiate an innate antiviral response via activation of interferon-beta production.
10. this study demonstrates for the first time that OV20.0 of Orf virus is also able to interact with the dsRNA binding domain of PACT and that the presence of dsRNA strengthened the interaction of these two molecules.