Rise of TRIM8: A Molecule of Duality
2020; Cell Press; Volume: 22; Linguagem: Inglês
10.1016/j.omtn.2020.08.034
ISSN2162-2531
Autores Tópico(s)Cancer Mechanisms and Therapy
ResumoThe human tripartite motif containing protein 8 (TRIM8), a member of TRIM family proteins, is known to play a dual role as both tumor suppressor and oncogene, and to function at the crosstalk of cancer and innate immunity. In this review, in addition to accumulating recent corroborations that endorse this dual character of TRIM8, we appraise the game-changing capacity of TRIM8 under stress conditions against the backdrop of cell proliferation, apoptosis, and cancer, and also highlight the duality of TRIM8 in multiple contexts like cellular localization, stress-induced conditions, and E3 ubiquitin ligase activity. Finally, we discuss the emerging role of TRIM8 during bipolar spindle formation and mitotic progression, and its growing sphere of influence across multiple human cancers and pathologies, and suggest TRIM8-linked axes that can be modulated further for anti-cancer therapeutics development. The human tripartite motif containing protein 8 (TRIM8), a member of TRIM family proteins, is known to play a dual role as both tumor suppressor and oncogene, and to function at the crosstalk of cancer and innate immunity. In this review, in addition to accumulating recent corroborations that endorse this dual character of TRIM8, we appraise the game-changing capacity of TRIM8 under stress conditions against the backdrop of cell proliferation, apoptosis, and cancer, and also highlight the duality of TRIM8 in multiple contexts like cellular localization, stress-induced conditions, and E3 ubiquitin ligase activity. Finally, we discuss the emerging role of TRIM8 during bipolar spindle formation and mitotic progression, and its growing sphere of influence across multiple human cancers and pathologies, and suggest TRIM8-linked axes that can be modulated further for anti-cancer therapeutics development. The human tripartite motif containing protein 8 (TRIM8) or RING finger protein 27 (RNF27), originally reported as glioblastoma expressed RING-finger protein (GERP),1Vincent S.R. Kwasnicka D.A. Fretier P. A novel RING finger-B box-coiled-coil protein, GERP.Biochem. Biophys. Res. Commun. 2000; 279: 482-486Crossref PubMed Scopus (26) Google Scholar is encoded by the TRIM8 gene (Ensembl: ENSG00000171206) and positioned on the chromosome 10q24.32, a region that is known to show frequent deletion or loss of heterozygosity in glioblastomas.1Vincent S.R. Kwasnicka D.A. Fretier P. A novel RING finger-B box-coiled-coil protein, GERP.Biochem. Biophys. Res. Commun. 2000; 279: 482-486Crossref PubMed Scopus (26) Google Scholar Since its discovery studies on TRIM8 have impacted multiple areas of cell and disease biology (Figure 1). In humans, TRIM8 is known to have a total of 15 splice-variant transcripts, and interestingly, three of them are uncharacterized long non-coding RNAs (lncRNAs) (Ensembl). TRIM8 is ubiquitously expressed in 27 human tissues considered in the Human Protein Atlas (HPA) RNA-Seq Project and produces one major transcript (Ensembl: ENST00000643721.1) of 7,290-bp length that codes for the 551-amino acid (aa) TRIM8 protein with a molecular mass of 61.489 kDa (UniProtKB: Q9BZR9 TRIM8 HUMAN). In the context of ubiquitin system, it is widely known that the conjugation reaction of ubiquitin to a substrate is catalyzed by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases.2Hershko A. Heller H. Elias S. Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown.J. Biol. Chem. 1983; 258: 8206-8214Abstract Full Text PDF PubMed Google Scholar The E3 ubiquitin ligases can be divided between two major classes: the homologous to E6-AP COOH terminus (HECT) E3 ubiquitin ligase family and the RING-finger-containing E3 ubiquitin ligase family. Although, TRIMs are considered among this RING-finger-containing E3 ubiquitin ligase family, not all TRIM E3 ubiquitin ligases have RING domains. For instance, in humans so far, the number of RING-less TRIM proteins stands at 9 out of more than 70 annotated TRIM proteins.3Hatakeyama S. TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.Trends Biochem. Sci. 2017; 42: 297-311Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar TRIM proteins play an important role in carcinogenesis and are highly associated with DNA repair, metastasis, tumor-suppressive regulation, and oncogenic regulation.3Hatakeyama S. TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.Trends Biochem. Sci. 2017; 42: 297-311Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar Further, some of the TRIM family proteins serve as critical regulators of autophagy and innate immunity and control important cellular processes, like intracellular signaling and transcription.3Hatakeyama S. TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.Trends Biochem. Sci. 2017; 42: 297-311Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 4Di Rienzo M. Romagnoli A. Antonioli M. Piacentini M. Fimia G.M. TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses.Cell Death Differ. 2020; 27: 887-902Crossref PubMed Scopus (25) Google Scholar, 5Ozato K. Shin D.M. Chang T.H. Morse 3rd, H.C. TRIM family proteins and their emerging roles in innate immunity.Nat. Rev. Immunol. 2008; 8: 849-860Crossref PubMed Scopus (628) Google Scholar TRIM8 belongs to this TRIM family of proteins (also called as RBCC proteins), which are known to maintain a common structural feature of having a tripartite motif, distinguished by the presence of a RING domain (R), one or two B-boxes (B), and a coiled-coil domain (CC).6Reymond A. Meroni G. Fantozzi A. Merla G. Cairo S. Luzi L. Riganelli D. Zanaria E. Messali S. Cainarca S. et al.The tripartite motif family identifies cell compartments.EMBO J. 2001; 20: 2140-2151Crossref PubMed Scopus (954) Google Scholar The human TRIM8, an E3 ubiquitin ligase protein, contains an N-terminal C3HC4-type RING-finger domain, followed by two B-boxes (Bbox1 and Bbox2), a coiled-coil domain,6Reymond A. Meroni G. Fantozzi A. Merla G. Cairo S. Luzi L. Riganelli D. Zanaria E. Messali S. Cainarca S. et al.The tripartite motif family identifies cell compartments.EMBO J. 2001; 20: 2140-2151Crossref PubMed Scopus (954) Google Scholar and a proline-rich no-domain C-terminal region with a monopartite nuclear localization signal (NLS)7Caratozzolo M.F. Marzano F. Mastropasqua F. Sbisà E. Tullo A. TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role.Genes (Basel). 2017; 8: 8Crossref Scopus (16) Google Scholar (Figure 2A). TRIM8 comes structurally under class V of TRIM-type proteins, along with TRIM19, TRIM31, TRIM40, TRIM56, TRIM73, TRIM74, RNF207, TRIM52, and TRIM61, which are also observed to have no known domains in their C-terminal region so far.5Ozato K. Shin D.M. Chang T.H. Morse 3rd, H.C. TRIM family proteins and their emerging roles in innate immunity.Nat. Rev. Immunol. 2008; 8: 849-860Crossref PubMed Scopus (628) Google Scholar,7Caratozzolo M.F. Marzano F. Mastropasqua F. Sbisà E. Tullo A. TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role.Genes (Basel). 2017; 8: 8Crossref Scopus (16) Google Scholar The RING domain of TRIM8 is crucial for its activity to regulate stabilization and activation TP53, degradation of MDM2,8Caratozzolo M.F. Micale L. Turturo M.G. Cornacchia S. Fusco C. Marzano F. Augello B. D'Erchia A.M. Guerrini L. Pesole G. et al.TRIM8 modulates p53 activity to dictate cell cycle arrest.Cell Cycle. 2012; 11: 511-523Crossref PubMed Scopus (41) Google Scholar and destabilization of ΔNp63α,9Caratozzolo M.F. Marzano F. Abbrescia D.I. Mastropasqua F. Petruzzella V. Calabrò V. Pesole G. Sbisà E. Guerrini L. Tullo A. TRIM8 Blunts the Pro-proliferative Action of ΔNp63α in a p53 Wild-Type Background.Front. Oncol. 2019; 9: 1154Crossref PubMed Scopus (3) Google Scholar and thus plays an important role in the context of cell proliferation, whereas the conserved B-box and coiled-coil domain region is known to mediate the interaction with SOCS1,10Toniato E. Chen X.P. Losman J. Flati V. Donahue L. Rothman P. TRIM8/GERP RING finger protein interacts with SOCS-1.J. Biol. Chem. 2002; 277: 37315-37322Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar a tumor suppressor gene.11Liau N.P.D. Laktyushin A. Lucet I.S. Murphy J.M. Yao S. Whitlock E. Callaghan K. Nicola N.A. Kershaw N.J. Babon J.J. The molecular basis of JAK/STAT inhibition by SOCS1.Nat. Commun. 2018; 9: 1558Crossref PubMed Scopus (102) Google Scholar The coiled-coil domain of TRIM8 is required for homodimerization,6Reymond A. Meroni G. Fantozzi A. Merla G. Cairo S. Luzi L. Riganelli D. Zanaria E. Messali S. Cainarca S. et al.The tripartite motif family identifies cell compartments.EMBO J. 2001; 20: 2140-2151Crossref PubMed Scopus (954) Google Scholar and deletion of the C-terminal domain of TRIM8 can result in protein mislocalization.6Reymond A. Meroni G. Fantozzi A. Merla G. Cairo S. Luzi L. Riganelli D. Zanaria E. Messali S. Cainarca S. et al.The tripartite motif family identifies cell compartments.EMBO J. 2001; 20: 2140-2151Crossref PubMed Scopus (954) Google Scholar TRIM8 can also interact with other TRIM proteins in humans, like TRIM2, TRIM8, TRIM9, TRIM15, TRIM21, TRIM24, TRIM25, TRIM27, TRIM39, TRIM43, TRIM44, and TRIM47.3Hatakeyama S. TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.Trends Biochem. Sci. 2017; 42: 297-311Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar Recent studies on TRIM8 strongly advocate for the critical role of TRIM8 as a regulator of cell proliferation9Caratozzolo M.F. Marzano F. Abbrescia D.I. Mastropasqua F. Petruzzella V. Calabrò V. Pesole G. Sbisà E. Guerrini L. Tullo A. TRIM8 Blunts the Pro-proliferative Action of ΔNp63α in a p53 Wild-Type Background.Front. Oncol. 2019; 9: 1154Crossref PubMed Scopus (3) Google Scholar,12Dang X. He B. Ning Q. Liu Y. Chang Y. Chen M. Suppression of TRIM8 by microRNA-182-5p restricts tumor necrosis factor-α-induced proliferation and migration of airway smooth muscle cells through inactivation of NF-Κb.Int. Immunopharmacol. 2020; 83: 106475Crossref PubMed Scopus (3) Google Scholar and as an important player in cancer,13Venuto S. Castellana S. Monti M. Appolloni I. Fusilli C. Fusco C. Pucci P. Malatesta P. Mazza T. Merla G. Micale L. TRIM8-driven transcriptomic profile of neural stem cells identified glioma-related nodal genes and pathways.Biochim. Biophys. Acta, Gen. Subj. 2019; 1863: 491-501Crossref PubMed Scopus (11) Google Scholar, 14Roy M. Tomar D. Singh K. Lakshmi S. Prajapati P. Bhatelia K. Gohel D. Singh R. TRIM8 regulated autophagy modulates the level of cleaved Caspase-3 subunit to inhibit genotoxic stress induced cell death.Cell. Signal. 2018; 48: 1-12Crossref PubMed Scopus (15) Google Scholar, 15Mastropasqua F. Marzano F. Valletti A. Aiello I. Di Tullio G. Morgano A. Liuni S. Ranieri E. Guerrini L. Gasparre G. et al.TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours.Mol. Cancer. 2017; 16: 67Crossref PubMed Scopus (32) Google Scholar, 16Liu Y. Zhang B. Shi T. Qin H. miR-182 promotes tumor growth and increases chemoresistance of human anaplastic thyroid cancer by targeting tripartite motif 8.OncoTargets Ther. 2017; 10: 1115-1122Crossref PubMed Scopus (23) Google Scholar immunity,17Maarifi G. Smith N. Maillet S. Moncorge O. Chamontin C. Edouard J. Sohm F. Blanchet F.P. Herbeuval J.-P. Lutfalla G. et al.TRIM8 is required for virus-induced IFN response in human plasmacytoid dendritic cells.Sci Adv. 2019; 5: eaax3511Crossref PubMed Scopus (21) Google Scholar and inflammation.18Bai X. Zhang Y.L. Liu L.N. Inhibition of TRIM8 restrains ischaemia-reperfusion-mediated cerebral injury by regulation of NF-κB activation associated inflammation and apoptosis.Exp. Cell Res. 2020; 388: 111818Crossref PubMed Scopus (8) Google Scholar Here, the duality of TRIM8 has been reviewed in multiple contexts, like its function and cellular localization, and the emerging role of TRIM8 during the course of cell cycle and bipolar mitotic spindle formation has been discussed. Further, TRIM8's growing sphere of influence has been assessed in the context of multiple human pathologies, and plausible approaches toward the development of anti-cancer therapeutics have been suggested. We showed that TRIM8 can act as a tumor suppressor by inducing TP53-dependent cell cycle arrest. TRIM8, a direct target gene of TP53, induces TP53 expression and tumor suppressor activity through a positive feedback loop-forming mechanism with TP53 during UV-instigated stress conditions by augmenting CDKN1A (p21) and GADD45 expression.8Caratozzolo M.F. Micale L. Turturo M.G. Cornacchia S. Fusco C. Marzano F. Augello B. D'Erchia A.M. Guerrini L. Pesole G. et al.TRIM8 modulates p53 activity to dictate cell cycle arrest.Cell Cycle. 2012; 11: 511-523Crossref PubMed Scopus (41) Google Scholar TRIM8 is highly downregulated in clear cell renal cell carcinoma (ccRCC), and the recovery of TRIM8 expression can lead to the enhancement of efficacy of chemotherapeutic drugs by re-activating the TP53 pathway, suggesting that TRIM8 can be used as an enhancer of chemotherapy efficacy in a TP53 wild-type background.19Caratozzolo M.F. Valletti A. Gigante M. Aiello I. Mastropasqua F. Marzano F. Ditonno P. Carrieri G. Simonnet H. D'Erchia A.M. et al.TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma.Oncotarget. 2014; 5: 7446-7457Crossref PubMed Scopus (35) Google Scholar Further, TRIM8 can restore the TP53 activity by blunting N-MYC activity in chemo-resistant tumors, like ccRCC and colorectal cancer (CRC), upon inhibition of miR-17-5p (also known as MIR17) and/or miR-106-5p. The inhibition of miR-17-5p and/or miR-106-5p leads to the recovery of TRIM8-mediated TP53 tumor suppressor activity and inhibits N-MYC-dependent cell proliferation through miR-34a upregulation.15Mastropasqua F. Marzano F. Valletti A. Aiello I. Di Tullio G. Morgano A. Liuni S. Ranieri E. Guerrini L. Gasparre G. et al.TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours.Mol. Cancer. 2017; 16: 67Crossref PubMed Scopus (32) Google Scholar Overall, these studies established an anti-proliferative image of TRIM8 during the course of cell proliferation and cancer, and, following the same trend, recent studies have also provided further evidence toward the anti-proliferative activity of TRIM8. It has recently been shown that TRIM8 can blunt the pro-proliferative action of oncogenic ΔNp63α in a TP53 wild-type background.9Caratozzolo M.F. Marzano F. Abbrescia D.I. Mastropasqua F. Petruzzella V. Calabrò V. Pesole G. Sbisà E. Guerrini L. Tullo A. TRIM8 Blunts the Pro-proliferative Action of ΔNp63α in a p53 Wild-Type Background.Front. Oncol. 2019; 9: 1154Crossref PubMed Scopus (3) Google Scholar Altogether, based on the current knowledge, it can be stated that TRIM8 has the capacity to exercise its anticancer power in three ways: by inducing the TP53 tumor suppressor activity through a positive feedback loop formation, restoring TP53 functions by blunting N-MYC activity in chemo-resistant tumors, and quenching the ΔNp63α oncogenic activity by forming a negative feedback loop. However, it should not go unnoticed that, in all three cases, TRIM8's anti-proliferative property is subject to the TP53 functional or wild-type background, suggesting a strong demand for research on TRIM8 and its anti-cancer capacity in a TP53 mutant background, as most of the TP53-associated axes (e.g., TP53-MDM2 axes) based on E3 ubiquitin ligase-targeting drugs fail in this caveat.20Huang X. Dixit V.M. Drugging the undruggables: exploring the ubiquitin system for drug development.Cell Res. 2016; 26: 484-498Crossref PubMed Scopus (248) Google Scholar Indeed, it would be of high importance to look at the capacity of TRIM8 to restore the native conformation of TP53 mutants and reactivate the tumor-suppressor function. In contrast to the anti-proliferative activity, TRIM8 can also work as an oncogenic protein.7Caratozzolo M.F. Marzano F. Mastropasqua F. Sbisà E. Tullo A. TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role.Genes (Basel). 2017; 8: 8Crossref Scopus (16) Google Scholar TRIM8 serves as a critical regulator of tumor necrosis factor alpha (TNF-α)- and interleukin (IL)-1β-induced nuclear factor κB (NF-κB) activation by mediating K63-linked polyubiquitination of TAK1, and overexpression of TRIM8 activates NF-κB and potentiates TNF-α- and IL-1β-induced activation of NF-κB, whereas knock down of TRIM8 brings opposite effects. Silencing of TRIM8 potentially inhibits TNFα gene expression in U937 cells (histiocytic lymphoma), indicating the oncogenic capacity of TRIM8.21Li Q. Yan J. Mao A.P. Li C. Ran Y. Shu H.B. Wang Y.Y. Tripartite motif 8 (TRIM8) modulates TNFα- and IL-1β-triggered NF-κB activation by targeting TAK1 for K63-linked polyubiquitination.Proc. Natl. Acad. Sci. USA. 2011; 108: 19341-19346Crossref PubMed Scopus (117) Google Scholar Further, TRIM8 positively regulates the TNF-induced NF-κB pathway at the p65 level by inducing the translocation of PIAS3 (protein inhibitor of activated STAT-3) from the nucleus to the cytoplasm.22Tomar D. Sripada L. Prajapati P. Singh R. Singh A.K. Singh R. Nucleo-cytoplasmic trafficking of TRIM8, a novel oncogene, is involved in positive regulation of TNF induced NF-κB pathway.PLoS ONE. 2012; 7: e48662Crossref PubMed Scopus (36) Google Scholar TRIM8 also regulates the clonogenic and migration ability of the cells through the NF-κB pathway, and knock down of TRIM8 in the breast cancer MCF7 cell line significantly decreases the cell proliferation and clonogenic potential of cells.22Tomar D. Sripada L. Prajapati P. Singh R. Singh A.K. Singh R. Nucleo-cytoplasmic trafficking of TRIM8, a novel oncogene, is involved in positive regulation of TNF induced NF-κB pathway.PLoS ONE. 2012; 7: e48662Crossref PubMed Scopus (36) Google Scholar Once activated, NF-κB promotes cell proliferation and protects cells from entering apoptosis. Thus, by positively regulating the TNF-induced NF-κB pathway, TRIM8 plays the role of an important oncogene that drives cell proliferation. Overall, from these two highly contrasting features, it can be stated that TRIM8 can function as both a tumor suppressor and an oncogenic molecule (Figure 2B). The duality of TRIM8 comes out under different stress conditions, like UV-instigated stress or genotoxic stress. Under exposure to UV, TP53 induces the expression of TRIM8, which, in turn, stabilizes TP53, leading to cell cycle arrest and reduction in cell proliferation through upregulation of CDKN1A (p21) and GADD45. Notably, TRIM8 silencing prevents TP53 activation after UV radiation. Further, the overexpression of TRIM8 reduces the half-life of MDM2, the key negative regulator of TP53, without altering MDM2 mRNA expression, which in turn results in an increased TP53 protein expression. Finally, it has also been proven that the TRIM8-RING domain is essential to regulate TP53 and MDM2 stability and activity. Overall, it suggests that, under UV-instigated stress conditions, TRIM8 plays an important role as a tumor suppressor to dictate cell cycle arrest.8Caratozzolo M.F. Micale L. Turturo M.G. Cornacchia S. Fusco C. Marzano F. Augello B. D'Erchia A.M. Guerrini L. Pesole G. et al.TRIM8 modulates p53 activity to dictate cell cycle arrest.Cell Cycle. 2012; 11: 511-523Crossref PubMed Scopus (41) Google Scholar In contradiction to this, a recent study has reported that TRIM8 can provide a survival advantage to cancer cells by enhancing autophagy flux through lysosomal biogenesis during genotoxic stress conditions. The study has shown TRIM8-regulated autophagy degrades the cleaved Caspase-3 subunit to inhibit genotoxic stress-induced cell death. TRIM8 knockdown reduces the expression of X-linked inhibitor of apoptosis protein (XIAP), whereas the enhanced expression of TRIM8 stabilizes XIAP during genotoxic stress conditions. XIAP also strongly activates NF-κB via BIR (baculovirus inhibitor of apoptosis protein repeat) domain-mediated dimerization and binding to TGF-β-activated kinase 1 (MAP3K7) binding protein 1 (Table 1). This XIAP-mediated NF-κB activation also induces expression of genes involved in autophagy, like Beclin-1. Interestingly, during genotoxic stress, TRIM8-mediated XIAP stabilization can also initiate inactivation of Caspase-3, one of the primary executioners of apoptotic cascade. Therefore, TRIM8-mediated XIAP stabilization has the capacity to bring two important oncogenic outcomes during the course of tumorigenesis. First, TRIM8-mediated XIAP stabilization can activate NF-κB, leading to expression of genes involved in autophagy and cell proliferation. Second, TRIM8 mediated stabilized XIAP prevents activation of Caspase-3, leading to the suppression of apoptosis. Through this novel mechanism, TRIM8 prevents cell death during genotoxic stress and radiation therapy,14Roy M. Tomar D. Singh K. Lakshmi S. Prajapati P. Bhatelia K. Gohel D. Singh R. TRIM8 regulated autophagy modulates the level of cleaved Caspase-3 subunit to inhibit genotoxic stress induced cell death.Cell. Signal. 2018; 48: 1-12Crossref PubMed Scopus (15) Google Scholar and this suggests TRIM8's highly potential oncogenic caliber can provide survival assistance to cancer cells. Historically, TRIM8 is considered to be among E3 ubiquitin ligases due to the presence of RING domain. Although the mechanism of activation of its E3 ubiquitin ligase activity is not known yet, TRIM8 has been shown to function as an E3 ubiquitin ligase in several important biological pathways. It is demonstrated that TRIM8 mediates K63-linked polyubiquitination of TGF-β-activated kinase 1 (TAK1), triggered by TNF-α and IL-1β, and, through this, TRIM8 serves as a critical regulator of TNF-α- and IL-1β-induced NF-κB activation.21Li Q. Yan J. Mao A.P. Li C. Ran Y. Shu H.B. Wang Y.Y. Tripartite motif 8 (TRIM8) modulates TNFα- and IL-1β-triggered NF-κB activation by targeting TAK1 for K63-linked polyubiquitination.Proc. Natl. Acad. Sci. USA. 2011; 108: 19341-19346Crossref PubMed Scopus (117) Google Scholar During Pseudomonas aeruginosa (PA)-induced keratitis infection, TRIM8 promotes K63-linked polyubiquitination of TAK1, leading to its activation and enhanced inflammatory responses.23Guo L. Dong W. Fu X. Lin J. Dong Z. Tan X. Zhang T. Tripartite Motif 8 (TRIM8) Positively Regulates Pro-inflammatory Responses in Pseudomonas aeruginosa-Induced Keratitis Through Promoting K63-Linked Polyubiquitination of TAK1 Protein.Inflammation. 2017; 40: 454-463Crossref PubMed Scopus (16) Google Scholar Ye et al.24Ye W. Hu M.M. Lei C.Q. Zhou Q. Lin H. Sun M.S. Shu H.B. TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Response by Blocking TRIF-TBK1 Interaction.J. Immunol. 2017; 199: 1856-1864Crossref PubMed Scopus (37) Google Scholar reported that TRIM8 can interact with Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) and mediates its K6- and K33-linked polyubiquitination, which leads to the disruption of the TRIF-TANK-binding kinase-1 association. In general, it is known that K63-linked ubiquitination is involved in regulating proteasome-independent functions, including cellular processes, like endocytosis and inflammatory immune responses, innate immunity, protein trafficking, and NF-κB signaling, whereas K6-linked polyubiquitination is known to be associated with DNA damage response and Parkin-mediated mitophagy, and K33-linked polyubiquitination is associated with TCR signaling, post Golgi-trafficking, and AMPK-related kinase signaling.25Akutsu M. Dikic I. Bremm A. Ubiquitin chain diversity at a glance.J. Cell Sci. 2016; 129: 875-880Crossref PubMed Scopus (211) Google Scholar Currently, it is experimentally well established that TRIM8 can perform K63-, K6-, and K33-linked polyubiquitination. TRIM8 also plays an important role in proteasomal degradation of SOCS1,10Toniato E. Chen X.P. Losman J. Flati V. Donahue L. Rothman P. TRIM8/GERP RING finger protein interacts with SOCS-1.J. Biol. Chem. 2002; 277: 37315-37322Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar although it has not been proven yet whether it is through TRIM8-mediated K48-linked ubiquitination or in association with other protein complexes. Nevertheless, TRIM8's E3 ubiquitin ligase activity and its involvement in cancer and immunity lies much beyond doubt. But, against this running flow, recent studies have reported that TRIM8 can not only act in an E3 ubiquitin ligase-independent manner, but it can also protect phosphorylated IRF7 (pIRF7) from proteasomal degradation through an E3 ubiquitin ligase-independent path by preventing its recognition by the peptidyl-prolyl isomerase Pin1.17Maarifi G. Smith N. Maillet S. Moncorge O. Chamontin C. Edouard J. Sohm F. Blanchet F.P. Herbeuval J.-P. Lutfalla G. et al.TRIM8 is required for virus-induced IFN response in human plasmacytoid dendritic cells.Sci Adv. 2019; 5: eaax3511Crossref PubMed Scopus (21) Google Scholar TRIM8 can function at two subcellular sites—nucleus and cytoplasm—to regulate NF-κB, one of the central signaling pathways that plays a critical role in carcinogenesis and inflammatory diseases. PIAS3 is known to negatively regulate the NF-κB pathway via its interaction with p65 in the nucleus. Expression of TRIM8 enhances NF-κB activity even in the presence of PIAS3, suggesting TRIM8 can inhibit PIAS3-mediated negative regulation of NF-κB.22Tomar D. Sripada L. Prajapati P. Singh R. Singh A.K. Singh R. Nucleo-cytoplasmic trafficking of TRIM8, a novel oncogene, is involved in positive regulation of TNF induced NF-κB pathway.PLoS ONE. 2012; 7: e48662Crossref PubMed Scopus (36) Google Scholar But TRIM8's ability to positively regulate NF-κB activity is not limited within the nucleus. Li et al.21Li Q. Yan J. Mao A.P. Li C. Ran Y. Shu H.B. Wang Y.Y. Tripartite motif 8 (TRIM8) modulates TNFα- and IL-1β-triggered NF-κB activation by targeting TAK1 for K63-linked polyubiquitination.Proc. Natl. Acad. Sci. USA. 2011; 108: 19341-19346Crossref PubMed Scopus (117) Google Scholar observed earlier that TRIM8 positively regulates the NF-κB pathway by K63-linked polyubiquitination of cytoplasmic protein TAK1. Following this, Tomar et. al.22Tomar D. Sripada L. Prajapati P. Singh R. Singh A.K. Singh R. Nucleo-cytoplasmic trafficking of TRIM8, a novel oncogene, is involved in positive regulation of TNF induced NF-κB pathway.PLoS ONE. 2012; 7: e48662Crossref PubMed Scopus (36) Google Scholar showed that TRIM8 can also regulate NF-κB activity in the cytoplasm under the influence of TNF-α. The study revealed that TNF-α induces the translocation of TRIM8 from the nucleus to the cytoplasm, which positively regulates NF-κB. A time-course study for TRIM8 nucleo-cytoplasmic translocation upon TNF treatment showed that TRIM8 translocates to the cytoplasm within 15 min and re-translocates back to the nucleus after 12 h.22Tomar D. Sripada L. Prajapati P. Singh R. Singh A.K. Singh R. Nucleo-cytoplasmic trafficking of TRIM8, a novel oncogene, is involved in positive regulation of TNF induced NF-κB pathway.PLoS ONE. 2012; 7: e48662Crossref PubMed Scopus (36) Google Scholar Another instance of TRIM8's nucleo-cytoplasmic translocation can be found in the regulation of STAT3 by PIAS3. In the cytoplasm, the ectopic expression of TRIM8 promotes proteasomal degradation of PIAS3, leading to the nuclear translocation of STAT3, whereas, in the nucleus, TRIM8 facilitates the recruitment of STAT3 to the STAT3-inducible element (SIE) regions of several brain- and cancer-related genes and binds to the SIE regions of the same genes.13Venuto S. Castellana S. Monti M. Appolloni I. Fusilli C. Fusco C. Pucci P. Malatesta P. Mazza T. Merla G. Micale L. TRIM8-driven transcriptomic profile of neural stem cells identified glioma-related nodal genes and pathways.Biochim. Biophys. Acta, Gen. Subj. 2019; 1863: 491-501Crossref PubMed Scopus (11) Google Scholar The regulation of STAT3 by TRIM8 via PIAS3 is extensively important in the context of glioblastoma. Zhang et al.26Zhang C. Mukherjee S. Tucker-Burden C. Ross J.L. Chau M.J. Kong J. Brat D.J. TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3.Mol. Oncol. 2017; 11: 280-294Crossref PubMed Scopus (28) Google Scholar reported that TRIM8 initiates STAT3 signaling to maintain stemness and self-renewal capacity in glioblastoma-like stem cells (GSCs) by suppressing the expression of PIAS3. Knockdown of TRIM8 reduces GSC self-renewal, whereas overexpression of TRIM8 leads to enhanced GSC self-renewal.26Zhang C. Mukherjee S. Tucker-Burden C. Ross J.L. Chau M.J. Kong J. Brat D.J. TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3.Mol. Oncol. 2017; 11: 280-294Crossref PubMed Scopus (28) Google Scholar The study has further shown that STAT3 activation can also upregulate TRIM8 expression, even in the setting of hemizygous gene deletion in glioblastoma, and this bi-directional positive feedback mechanism facilitates stemness in GSCs. This suggests that TRIM8 acts as an oncogenic molecule by promoting the self-renewal capacity of GSCs. In contrast, we showed that the downregulation of TRIM8 in glioblastoma compared to its normal counterpart is indeed associated with a significant increase in the risk of disease progression in patients. Most importantly, TRIM8 overexpression and restored TRIM8 expression significantly reduce both cell proliferation and clonogenic potential in glioma cells, suggesting the anti-proliferative capacity of TRIM8 in glioma patients.27Micale L. Fusco C. Fontana A. Barbano R. Augello B. De Nittis P. Copetti M. Pellico M.T. Mandriani B. Cocciadiferro D. et al.TRIM8 downregulation in glioma affects
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