TRIM32(Kr.9q33.1) ;LGMD2H, HT2A, BBS11, TAT1P (C_VII)

Tämä TRIM32  kuuluu rakenteeltaan luokkaan CII eli siinä on  tyypillisten  N-terminalisten  domaanien (RING, BBox1, BBox2, C-C)  lisäksi  C-terminaalissa konservoitunut   NHL- domaani.On havaittu tämän proteiinin lokalisoituvan sytoplasmisiin kappaleisiin  (CB) Niissä  sen TRIM32 funktio on liukenemattomasa  ja inaktiivissa muodossa. Tätä ilmeisesti   retrovirus HIV-1 käyttää hyväksi ja  lokalisoituu näihin inaktiiveihin  HSP-TRIM32 sisältäviin kappaleisiin  Tat - aktivaatiodomaanilla. 

TRIM32  on nissä CB-kappaleissa  kvaliteettikontrollipakkauksessa.  Mutta se voi olla myös  14-3-3 kompleksina  fosforyloituneena liukoisessa muodossa tai sitten  se voi olla  aktivoitusmiskykyisenä  sytoplasmassa.Se on p53 kohdemolekyyli solustressissä ja säätyy ylös  p53 vaikutuksesta.  Puolestaan  se taas säätää negatiivisesti p53:n.  RNA ja DNA viruksiin  TRIM53 vastaa vahvistamlla STINGvälitteisen  IFNbeta tuotannon.   Sydänlihaksessa dysbindiini  on proeiini, jota  TRIM53 säätelee.

https://www.ncbi.nlm.nih.gov/gene/22954

HT2A; BBS11; TATIP; LGMD2H

Summary

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. The protein has also been localized to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein. The Tat protein activates transcription of HIV-1 genes. [provided by RefSeq, Jul 2008]

Expression Ubiquitous expression in endometrium (RPKM 1.6), adrenal (RPKM 1.5) and 24 other tissues See more

TRIM32 ja silmän sarveiskalvon herpeskeratitis

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

• TRIM32 as a crucial positive regulator of Herpes Simplex Virus type 1 (HSV-1) induced IFN-beta production in corneal epithelial cells, and it played a predominant role in clearing HSV-1 from the cornea.

• (Suomennosta) Silmän sarveiskalvon epiteelisolut ovat tärkeä este suojaamassa sarveiskalvoa patogeenisten mikrobien infektioilta. Mikä on TRIM32:n merkitys tässä suojauksessa? Herpes simplex-1 viruksen tunnsituksesta silmän sarveiskalvossa TRIM32 lisääntyi. (TRIM32 poistogeenisyys pahensi tilanteen herpeskeratiitiksi ja virus pääsi lisääntymään. Jos taas TRIM32 hiljennettiin, interferonibeetan ilmenemä aleni ja IRF3 aktivaatio vaimeni.) Havaittiin että TRIM32 sääteli positiivisesti sarveiskalvoepiteelin interferoni-beetan tuotantoa edistämällä inerferonigeenien stimulaattorin (STING) K63:n ubikitinaatiota, josta seurasi välillisesti IRF3 tehostunut aktivaatio ja sen jälkeen IFN beetan tuotanto.

• Epithelial cells play important roles as a critical barrier in protecting the cornea from microbial pathogens infection. In this study, we were aiming to investigate the role of E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) in corneal epithelial cells in response to Herpes Simplex Virus type 1 (HSV-1) infection and to elucidate the underlying mechanisms. We found the expression of TRIM32 was increased after infected with HSV-1 both in murine corneas and cultured human epithelial (HCE) cells. Furthermore, knockdown of the expression of TRIM32 significantly aggravated HSV-1 induced herpetic stromal keratitis (HSK) in mice and promoted the replication of HSV-1 in cultured HCE cells. We also observed that silencing of TRIM32 resulted in the decreased expression of IFN-β and suppressed activation of interferon regulatory factor 3 (IRF3) both in vivo and in vitro. Finally, we found TRIM32 positively regulate IFN-β production in corneal epithelial cells through promoting K63-linked polyubiquitination of stimulator of interferon genes (STING).

TRIM32-proteiini kvaliteettikontrollissa

1. HSP70-TRIM32 complex is biochemically distinct from the previously characterized 14-3-3-TRIM32 phospho-complex.

• (Suomennosta) Proteiinien aggrekoitumisen spontaani ja energiaa vapauttava reaktio estyy soluissa tyypillisesti solun laadunkontrollikoneistolla (QC). TRIM32 on E3 ubikitiiniligaasi ja muodostaa ylirunsaana esiintyessään helposti proteosomien estämättä pallomaisia inkluusioita, joita sanotaan sytoplasmisiksi kappaleiksi (CB) . Keskeinen laadunkontrollijärjestelmän komponentti on HSP70 ja se ensisijassa sitoo liikamäärää TRIM32 proteiinia. On kuitenkin yllätys, että tämä molekulaarinen kaitsijamolekyyli nopeuttaa ja stabiloi sytoplasmisien kappaleiden koostamista solunsisäisestä ATPaasista riippuvalla tavalla pikemminkin kuin yrittäisi estää CB-kappaleiden muodostusta. Havaitaan myös että HSP70-Trim32 -kompleksi on biokemiallisesti erilainen kuin toisessa artikkelissa kuvattu 14-3-3-TRIM32- fosfokompleksi. Lisäksi näillä kahdella kompleksilla on päinvastaiset vaikutuksetkin. HSP70 stimuloi liukenemattomien inaktiivien CB-kompleksien mudostusta ja 14-3-3 taas pitää TRIM32 liukoisena inaktiivina kompleksina. Tutkijoiden johtopäätös on, että CB inkluusioiden muodostus on solun kvaliteettikontrollijärjestelmän aktiivisti kontrolloimaa ja vaatii ATP:tä, kuten myös proteiinien normaalit laskostus ja hajoitusreaktiot.

• The spontaneous and energy-releasing reaction of protein aggregation is typically prevented by cellular quality control machinery (QC). TRIM32 is a member of the TRIM (tripartite motif-containing) ubiquitin E3 ligases, and when overexpressed in cultured cells, readily forms spherical inclusions designated as cytoplasmic bodies (CBs) even without proteasome inhibition. Here, we show that HSP70, a central QC component, is a primary binding factor of overexpressed TRIM32. Contrary to expectation, however, we find that this molecular chaperone facilitates and stabilizes CB assembly depending on intrinsic ATPase activity, rather than preventing CB formation. We also show that the HSP70-TRIM32 complex is biochemically distinct from the previously characterized 14-3-3-TRIM32 phospho-complex. Moreover, the two complexes have opposing roles, with HSP70 stimulating CB formation and 14-3-3 retaining TRIM32 in a diffuse form throughout the cytosol. Our results suggest that CB inclusion formation is actively controlled by cellular QC and requires ATP, similar to protein folding and degradation reactions. 
   
  
  
  
  
  
  
  
  
   

  TRIM32 ja kohdemolekyyli dysbindiini

• Data suggest that, in cardiomyocytes, TRIM32 attenuates activation of SRF signaling and hypertrophy due to dysbindin; TRIM24 promotes these effects. TRIM32 promotes dysbindin degradation; TRIM24 protects dysbindin from degradation. (TRIM = tripartite motif-containing protein; SRF = serum response factor)

• (Suomennosta) Dysbindin (costameerin rakenteellinen komponentti) on vahva indusoija sydänlihassolun hypertrofiassa Rho/SRF signaloinnin kautta. Sydämen dysbindiinin interaktomissa havaittiin TRIM24 ja TIM32. TRIM32 toimii dysbindiinin E3ubikitiiniligaasina luurankolihaksessa. Se hajoitti myös neonataalista sydänkammiolihasta ( koe-eläimessä) . TRIM24 sensijaan suojeli dysbindiiniproteiinia TRIM32:n aiheutamalta hajoitukselta. Johdonmukaisesti TRIM32 myös vaimensi SRF välittiestä aktivaatioa ja dysbindiinista johtuvaa hypertrofiaa ja TRIM24 taas vaikutti kammiomyosyytin hypertrofiaa. TRIM32 on kardiomyosyytin elinkykyisyyden ja apoptoosin avainsäätelijä samanaikaisesti akivoiden p53 ja kaspaasti -3/-7 apoptoosin X-linkkiytyneen inhibiitorin.
• We have previously shown that dysbindin is a potent inducer of cardiomyocyte hypertrophy via activation of Rho-dependent serum-response factor (SRF) signaling. We have now performed a yeast two-hybrid screen using dysbindin as bait against a cardiac cDNA library to identify the cardiac dysbindin interactome. Among several putative binding proteins, we identified tripartite motif-containing protein 24 (TRIM24) and confirmed this interaction by co-immunoprecipitation and co-immunostaining. Another tripartite motif (TRIM) family protein, TRIM32, has been reported earlier as an E3 ubiquitin ligase for dysbindin in skeletal muscle. Consistently, we found that TRIM32 also degraded dysbindin in neonatal rat ventricular cardiomyocytes as well. Surprisingly, however, TRIM24 did not promote dysbindin decay but rather protected dysbindin against degradation by TRIM32. Correspondingly, TRIM32 attenuated the activation of SRF signaling and hypertrophy due to dysbindin, whereas TRIM24 promoted these effects in neonatal rat ventricular cardiomyocytes. This study also implies that TRIM32 is a key regulator of cell viability and apoptosis in cardiomyocytes via simultaneous activation of p53 and caspase-3/-7 and inhibition of X-linked inhibitor of apoptosis. In conclusion, we provide here a novel mechanism of post-translational regulation of dysbindin and hypertrophy via TRIM24 and TRIM32 and show the importance of TRIM32 in cardiomyocyte apoptosis in vitro.
• Duchenne muscular dystrophy muscles showed a selective up-regulation of the ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). The induction of TRIM32 was due to a transcriptional effect and it correlated with disease severity.
• we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity
• that TRIM32 plays a protective role in aortic banding-induced pathological cardiac remodelling by blocking Akt-dependent signalling
• these findings suggest that TRIM32 might play important roles in the hepatocarcinogenesis.
• results show a novel molecular cascade involving miR-155 and TRIM32 leading to HIV-1 Tat-induced attenuated proliferation of neural precursor cells; study also uncovered an unidentified role for miR-155 in modulating human neural stem cell proliferation, helping in better understanding of neural precursor cells and diseased brain

TRIM32 kuuluu TRIM-NHL proteiinijoukkoon (C_VII)

• Studies indicate most-studied TRIpartite Motif (TRIM)-NHL proteins TRIM2, TRIM3, TRIM32 and TRIM71, and their mutations have been linked to diseases.
  ( Suomennosta. Tämä TRIM 32 kuuluu rakenteelliseti niihin TRIM-operheen jseniin jossa on C-terminaalisia NHL- jaksoja. Tämä artikke mainitsee nisitä TRIM2, -3, -32, -71.
• TRIM-NHL proteins are key regulators of developmental transitions, for example promoting differentiation, while inhibiting cell growth and proliferation, in stem and progenitor cells. Abnormalities in these proteins have been also associated with human diseases, particularly affecting muscular and neuronal functions, making them potential targets for therapeutic intervention. The purpose of this review is to provide a systematic and comprehensive summary on the most studied TRIM-NHL proteins, highlighting examples where connections were established between structural features, molecular functions and biological outcomes. (TRIM2/ CMT2R); (TRIM3/BERP)(TRIM32/ LGMD2H, BBS11,TAT1P,HT2A)(TRIM71/LIN-41)

TRIM53 on p53:n kohdemolekyyli ja sen negatiivinen säätelijä

• https://www.ncbi.nlm.nih.gov/pubmed/25146927Cell Death Differ. 2014 Nov;21(11):1792-804. doi: 10.1038/cdd.2014.121. Epub 2014 Aug 22. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. Liu J¹, Zhang (Suomennosta) Tuumorisuppressori p53 omaa avainosaa genomisen stabiliteetin ylläpidossa ja tuumorinmuodostumsiten estämisessä säätelemällä solun stressivasteit, apoptoosia, solusyksin pysäyttämistä ja solun vanhenemista. P53;n sopivan solupitoisuuden ja funktion säätely on solulle tärkeää ja on tiukasti säädelty postttranslationaalisin modifikaatioin, joihin myös ubikitinaatio kuuluu. TRIM32 on yt tunnsitettu uutena p53:n kohdegeeninä ja p53:n negatiivisena säätelijänä, joka säätelee p53-välitteistä stressivastetta. Kun jokin stressi kohtaa solua, esim DNA vaurio, p53 sitoutuu TRIM23 geenin promoottorin siihen kohtaan joka on p53- responsiivinen elementti ja niin solu alkaa tuottaa TRIM32-proteiinia. Mutta nyt puolestaan nämä uudet runsaat TRIM32 proteiinit kohdentuvat p53 proteiiniin ja ubikitinoivat sen ja lähettävät silppuroitavaksi. Näin TRIM32 saa säädeltyä alas p53-välitteisen apoptoosin , solusyklin pysähtymän ja solunvanhenemisprosessin, joita stressistä seurasi. Toisaalta taas moni tuumori hankkii itselleen TRIM32 kykyjä ja TRIM32 ilmenemä on niissä kohonnut. Ylimäärin esiintyvä TRIM32 ( joka on isontäkehon proteiinin laatukontrollin ulottumattomissa) edistää onkogeenista transformaatiota ja tumorigeneesiä – lähinnä p53- riippuvalla tavalla. Tulokset selvittävät TRIM32:n uudeksi p53-kohdemolekyyliksi ja p53:n negatiiviseksi säätelijäksi. TRIM32 on tärkeä p53:n ja p53- välitetisten solun stressivasteiden säätelijä. TRIM32:sta johtuva p53- funktioiden vikaantuminen on uusi havaittu tuumorien syntymismekanismi.
• AbstractTumor suppressor p53 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post-translational modifications, such as ubiquitination. Here, we identified E3 ubiquitin ligase TRIM32 as a novel p53 target gene and negative regulator to regulate p53-mediated stress responses. In response to stress, such as DNA damage, p53 binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 interacts with p53 and promotes p53 degradation through ubiquitination. Thus, TRIM32 negatively regulates p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. TRIM32 is frequently overexpressed in different types of human tumors. TRIM32 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53-dependent manner. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 has an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results also revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis.

• Results suggest that Salmonella effector SseK3 binding to host tripartite motif-containing 32 protein (TRIM32) in the inhibition of nuclear factor kappa B (NF-kappaB) activation: [SseK3]
  

TRIM32 ubikitinoi STING-adaptorin vahvistaen IFN beetan indusoitumista amtivirusvasteena RNA ja DNA viruksille

• Biol Chem. 2012 Aug 17;287(34):28646-55. doi: 10.1074/jbc.M112.362608. Epub 2012 Jun 28.TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination.Zhang J¹, Hu MM, Wang YY, Shu HB Abstract Viral infection activates several transcription factors including NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. MITA (also called STING) is a critical adaptor protein that links virus-sensing receptors to IRF3 activation upon infection by both RNA and DNA pathogens. Here we show that the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) ubiquitinated MITA and dramatically enhanced MITA-mediated induction of IFN-β. Overexpression of TRIM32 potentiated virus-triggered IFNB1 expression and cellular antiviral response. Consistently, knockdown of TRIM32 had opposite effects. TRIM32 interacted with MITA, and was located at the mitochondria and endoplasmic reticulum. TRIM32 targeted MITA for K63-linked ubiquitination at K20/150/224/236 through its E3 ubiquitin ligase activity, which promoted the interaction of MITA with TBK1. These findings suggest that TRIM32 is an important regulatory protein for innate immunity against both RNA and DNA viruses by targeting MITA for K63-linked ubiquitination and downstream activation.

TRIM32 ja 14-3-3 muodostavat sytoplasmassa inaktiivin liukoisen kompleksin

• Cell Sci. 2013 May 1;126(Pt 9):2014-26. doi: 10.1242/jcs.122069. Epub 2013 Feb 26.14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitylation and cytoplasmic body formation.Ichimura T¹, Taoka M, Shoji I, Kato H, Sato T, Hatakeyama S, Isobe T, Hachiya N. Abstract Deregulated expression of tripartite motif-containing protein 32 (TRIM32, an E3 ubiquitin-protein ligase) contributes to various diseases. Here we report, using quantitative proteomics and biochemistry, that 14-3-3 proteins bind to phosphorylated TRIM32 and prevent TRIM32 autoubiquitylation and the formation of TRIM32-containing cytoplasmic bodies, which are potential autoregulatory mechanisms that can reduce the concentration of soluble free TRIM32. The 14-3-3-TRIM32 interaction is dependent on protein-kinase-A-catalyzed phosphorylation of TRIM32 at Ser651. We found that the inhibitory effect of 14-3-3 is, in part, a consequence of disrupting the propensity of TRIM32 to undergo higher-order self-association without affecting its dimerization. Consequently, dimerized TRIM32 bound to 14-3-3 was sequestered in a distinct cytoplasmic pool away from the microtubule network, whereas a TRIM32 mutant that cannot bind 14-3-3 underwent multimerization and was unavailable to facilitate cell growth. Our results reveal a novel connection between ubiquitylation and phosphorylation pathways, which could modulate a variety of cell events by stimulating the formation of the 14-3-3-TRIM32 signaling complex. KEYWORDS: 14-3-3; PKA; Phosphorylation; TRIM32; Ubiquitylation

Muistiin 10.4. 2019