TRIM14 inhibits hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein

Wang, Shanshan; Chen, Yongzhi; Li, Chunfeng; Wu, Yiming; Guo, Lei; Peng, Changwei; Huang, Yueping; Cheng, Genhong; Qin, F. Xiao-Feng

doi:10.1038/srep32336

Cited by 57 publications

(67 citation statements)

References 46 publications

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“…Because previous studies have implicated the TRIMs as critical regulators in innate immune responses, we hypothesized that TRIM14 may exert antitumor cell effects via interferon signaling pathways in lung cancer cells816. Downregulation of TRIM14 attenuated interferon-γ (IFNγ)-induced activation of signal transducer and activator of transcription 1 (STAT1) phosphorylation at tyrosine 701 in cells over time.…”

Section: Resultsmentioning

confidence: 99%

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

Hai

Zhu

Wang

et al. 2017

Sci Rep

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Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC. Little is known about the function of TRIM14 protein in normal or disease states. We investigated the functional and prognostic role of TRIM14 in NSCLC using in vitro and in vivo perturbation model systems. Firstly, a pooled RNAi screen identified TRIM14 to effect cell proliferation/survival in NSCLC cells. Secondly, silencing of TRIM14 expression significantly enhanced tumor growth in NSCLC xenograft mouse models, while exogenous TRIM14 expression attenuated tumorigenesis. In addition, differences in apoptotic activity between TRIM14-deficient and control tumors suggests that TRIM14 tumor suppressor activity may depend on cell death signaling pathways. TRIM14-deficient cell lines showed both resistance to hypoxia-induced cell death and attenuation of interferon response via STAT1 signaling. Consistent with these phenotypes, multivariate analyses on published mRNA expression datasets of over 600 primary NSCLCs demonstrated that low TRIM14 mRNA levels are significantly associated with poorer prognosis in early stage NSCLC patients. Our functional data therefore establish a novel tumor suppressive role for TRIM14 in NSCLC progression.

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Section: Resultsmentioning

confidence: 99%

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

Hai

Zhu

Wang

et al. 2017

Sci Rep

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“…Among the newly identified anti-listerial ISGs, TRIM14 exhibited the greatest inhibitory activity (Fig 2E). Interestingly, this protein has recently been linked to antiviral defense through several independent mechanisms ([36–38]) but has not been previously implicated in antibacterial immunity.…”

Section: Resultsmentioning

confidence: 99%

Cell-Based Screen Identifies Human Interferon-Stimulated Regulators of Listeria monocytogenes Infection

et al. 2016

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The type I interferon (IFN) activated transcriptional response is a critical antiviral defense mechanism, yet its role in bacterial pathogenesis remains less well characterized. Using an intracellular pathogen Listeria monocytogenes (Lm) as a model bacterial pathogen, we sought to identify the roles of individual interferon-stimulated genes (ISGs) in context of bacterial infection. Previously, IFN has been implicated in both restricting and promoting Lm growth and immune stimulatory functions in vivo. Here we adapted a gain-of-function flow cytometry based approach to screen a library of more than 350 human ISGs for inhibitors and enhancers of Lm infection. We identify 6 genes, including UNC93B1, MYD88, AQP9, and TRIM14 that potently inhibit Lm infection. These inhibitors act through both transcription-mediated (MYD88) and non-transcriptional mechanisms (TRIM14). Further, we identify and characterize the human high affinity immunoglobulin receptor FcγRIa as an enhancer of Lm internalization. Our results reveal that FcγRIa promotes Lm uptake in the absence of known host Lm internalization receptors (E-cadherin and c-Met) as well as bacterial surface internalins (InlA and InlB). Additionally, FcγRIa-mediated uptake occurs independently of Lm opsonization or canonical FcγRIa signaling. Finally, we established the contribution of FcγRIa to Lm infection in phagocytic cells, thus potentially linking the IFN response to a novel bacterial uptake pathway. Together, these studies provide an experimental and conceptual basis for deciphering the role of IFN in bacterial defense and virulence at single-gene resolution.

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“…TRIM14 and TRIM22 are two TRIMs that function as ISGs during hepatitis C virus (HCV) infection [78,79]. The presence of either TRIM14 or TRIM22 conferred restriction against HCV replication that depended on an interaction with the viral NS5A protein in both cases [78,79]. This interaction resulted in the destruction of the viral NS5A by ubiquitination and subsequent proteasome targeting [78,79].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

“…The presence of either TRIM14 or TRIM22 conferred restriction against HCV replication that depended on an interaction with the viral NS5A protein in both cases [78,79]. This interaction resulted in the destruction of the viral NS5A by ubiquitination and subsequent proteasome targeting [78,79]. Although TRIM14 is known to function as a mitochondrial adaptor for IFN and NF-κB signalling, usage of the TRIM14 mutant that fails to mediate innate immune signalling (K365R) revealed restriction against HCV was unaltered [78].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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TRIM14 inhibits hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein

Cited by 57 publications

References 46 publications

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

Cell-Based Screen Identifies Human Interferon-Stimulated Regulators of Listeria monocytogenes Infection

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

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