The E3 Ubiquitin Ligase RNF5 Targets Virus-Induced Signaling Adaptor for Ubiquitination and Degradation

Zhong, Bo; Zhang, Yu; Tan, Bo; Liu, Tiantian; Wang, Yan-Yi; Shu, Hong‐Bing

doi:10.4049/jimmunol.0903748

Cited by 146 publications

(119 citation statements)

References 33 publications

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“…Besides, PCBP1 displays some regulatory effects after viral infection ( Figures 3D and 6). In either case, the engagement of PCBP1 is crucial because of one thing, effective suppression of IFN-α/β may only be possible with the concerted actions of several suppressors, and for the other, unlike those stimulus-triggered inhibitors including PCBP2 [6,22,35,[47][48][49][50][51][52][53], PCBP1 may serve to tune the threshold for initiation of signal transduction by restricting MAVS at basal conditions [54,55]. The latter feature of PCBP1 is of special importance in preventing various inflammatory disorders caused by unwanted IFN [33,[56][57][58] as a result of possible activities of excessive MAVS.…”

Section: Discussionmentioning

confidence: 99%

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

et al. 2011

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Mitochondrial antiviral signaling (MAVS) is a key adaptor in cellular antiviral innate immunity. We previously identified poly(C)-binding protein 2 (PCBP2) as a feedback inhibitor of MAVS that facilitates its degradation after viral infection, but little is known about the regulatory potential of poly(C)-binding protein 1 (PCBP1), which highly resembles PCBP2. Here we report that PCBP1 mediates housekeeping degradation of MAVS using the same mechanism as PCBP2 employs. Overexpression of PCBP1 impairs MAVS-mediated antiviral responses, while knockdown of PCBP1 exerts the opposite effect. The suppression is due to PCBP1-induced MAVS degradation. We observe that PCBP1 and PCBP2 show synergy in MAVS inhibition, but their expression patterns are distinct: PCBP1 is stably and abundantly expressed, while PCBP2 shows low basal expression with rapid induction after infection. Individual knockdown and subcellular fractionation analyses reveal that unlike the postinfection inhibitor PCBP2, PCBP1 continuously eliminates cellular MAVS. Our findings unravel a critical role of PCBP1 in regulating MAVS for both finetuning the antiviral immunity and preventing inflammation.

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Section: Discussionmentioning

confidence: 99%

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

et al. 2011

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“…Reimmunoprecipitation experiments were performed as described (38,39). Briefly, after first-round immunoprecipitation, the immunoprecipitates were reextracted in lysis buffer containing 1% SDS and denatured by heating for 5 min.…”

Section: Methodsmentioning

confidence: 99%

The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation

Chen

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The proinflammatory cytokine interleukin-1 (IL-1) signals via type I IL-1 receptor (IL-1RI) and IL-1 receptor accessory protein (IL1RAP), which leads to activation of the transcription factor NF-κB and induction of a range of downstream proteins involved in inflammatory and immune responses. Here, we identified the E3 ubiquitin ligase membrane-associated RING-CH (MARCH8) as a suppressor of IL-1β-induced NF-κB-and MAPK-activation pathways. Overexpression of MARCH8 inhibits IL-1β-induced NF-κB and MAPK activation, whereas knockdown of MARCH8 has the opposite effect. Mechanistically, MARCH8 interacts with IL1RAP and targets its Lys512 for K48-linked polyubiquitination and degradation. Our findings suggest that MARCH8-mediated polyubiquitination and degradation of IL1RAP is an important mechanism for negative regulation of IL-1β-induced signaling pathways.T he transcription factor NF-κB plays pivotal roles in many aspects of cellular processes such as inflammation, innate immunity, and cancer. NF-κB is sequestered in the cytoplasm and kept inactive in nonstimulated cells by binding to inhibitory IκB (inhibitor of κB) proteins. Under stimulation with cytokines, infectious pathogens, or genotoxic stresses, the IκB proteins are phosphorylated, ubiquitinated, and ultimately degraded, which frees NF-κB for translocation into the nucleus, where it induces transcription of downstream target genes (1-3).Interleukin 1 (IL-1) is a critical proinflammatory cytokine that can trigger a cascade of signaling leading to activation of NF-κB. It functions through engagement of two membrane-bound receptors: IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL1RAP) (4-6). IL-1RI is the ligand-recognition receptor that binds IL-1β directly (7). Although IL1RAP does not bind IL-1β directly, its recruitment to IL-1RI following IL-1β stimulation is essential for the formation of an activated membrane receptor complex (8-10). The activated complex can then recruit intracellular adaptor proteins and kinases, including MyD88, IRAK4,. IRAK4 phosphorylates and activates IRAK1, which in turn recruits TRAF6. IRAK1 and TRAF6 form a complex that is released from the receptor complex (15, 16). TRAF6 possesses an E3 ubiquitin ligase activity that mediates its autoubiquitination. Ubiquitinated TRAF6 further recruits the TGF-b-activated kinase 1 (TAK1)-TAK1-binding protein 2 (TAB2)-TAB3 complex, resulting in the activation of TAK1. Activated TAK1 subsequently activates downstream kinases IKK-α and IKK-β, which phosphorylate IκB proteins, and lead to activation of NF-κB (17).Several studies have suggested that ubiquitination is a central rhythm of regulation of IL-1β-induced NF-κB activation pathways. It has been shown that the E3 ubiquitin ligase TRAF6 mediates K63-linked polyubiquitination of IRAK1 for recruiting IKK and activating NF-κB (18). Tripartite motif 8 (TRIM8) catalyzes K63-linked polyubiquitination of TAK1, and this promotes the activation of TAK1 (19). It has also been demonstrated that the E3 ligase Pellino 3b acts as a n...

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“…TRAF3 is a key molecule in the cascade of RIG-I signaling pathway, and its K63-linked polyubiquitination is required for TBK1 recruitment and downstream events; additionally, the regulation of different forms of polyubiquitination chains emerged as critical to the regulation of innate immunity pathways (14,(27)(28)(29)(30)(31). To further elucidate the biochemical mechanisms, we investigate the impact of WDR82 in regulating TRAF3 polyubiquitination.…”

Section: Wdr82 Enhances K48-linked Polyubiquitination Of Traf3mentioning

confidence: 99%

WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines

Zhu

Wang

et al. 2015

The Journal of Immunology

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Upon virus infection, retinoic acid–inducible gene I–like receptors in host cells recognize viral RNA and activate type I IFN expression. Previously, we identified WD repeat domain (WDR) 5 as one positive regulator for pathway activation. In this study, we report that WDR82, a homolog protein of WDR5, acts opposite to WDR5 and inhibits the activation of the retinoic acid–inducible gene I signaling pathway. WDR82 overexpression inhibits virus-triggered pathway activation, whereas its knockdown enhances induced IFN-β expression. WDR82 is localized on the mitochondria, and its first N-terminal WD40 domain is critical for localization. WDR82 interacts with TNFR-associated factor (TRAF) 3, and its overexpression promotes K48-linked, but not K63-linked, polyubiquitination on TRAF3. Furthermore, WDR82 knockdown inhibits viral replication in the cell, whereas its overexpression has the opposite effect. Interestingly, WDR82 regulates Sendai virus–induced IFNB1 expression in a cell type–specific manner. Taken together, our findings demonstrate that WDR82 is a negative regulator of virus-triggered type I IFNs pathway through mediating TRAF3 polyubiquitination status and stability on mitochondria.

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The E3 Ubiquitin Ligase RNF5 Targets Virus-Induced Signaling Adaptor for Ubiquitination and Degradation

Cited by 146 publications

References 33 publications

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation

WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines

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