NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25

Chen, Szu Ting; Chen, Liang; Lin, Diego Shih Chieh; Chen, Sei Yi; Tsao, Yen Po; Guo, Haitao; Li, Fei Ju; Tseng, Wei‐Ting; Tam, Jason W.; Chao, Chien-Ming; Brickey, W. June; Dzhagalov, Ivan; Song, Mee Hyun; Kang, Hye Ri; Jung, Jae U.; Ting, Jenny P.Y.

doi:10.1016/j.chom.2019.02.013

Cited by 71 publications

(65 citation statements)

References 53 publications

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“…Consistently, higher inflammatory responses in Nlrp12 -/mice during Salmonella Typhimurium infection helped resolve the infection [70]. A recent study demonstrated that NLRP12 dampens antiviral immune responses; however, such a regulation involved the RIG-I pathway but not NF-κB and MAPK [75], suggesting that NLRP12 may regulate inflammatory response and host immunity in multiple ways.…”

Section: Nlrp12 and Inflammatory Disordersmentioning

confidence: 80%

Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma

Khan

Zaki

2020

IJMS

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Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is initiated and promoted by chronic inflammation. Inflammatory mediators are transcriptionally regulated by several inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). cJun N-terminal kinase (JNK), a member of the MAPK family, plays a central role in HCC pathogenesis. Pathogen-associated molecular patterns (PAMPs) activate JNK and other MAPK upon recognition by toll-like receptors (TLRs). Apart from TLRs, PAMPs are sensed by several other pattern recognition receptors, including cytosolic NOD-like receptors (NLRs). In a recent study, we demonstrated that the NLR member NLRP12 plays a critical role in suppressing HCC via negative regulation of the JNK pathway. This article briefly reviews the crosstalk between NLRP12 and JNK that occurs during HCC.

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Section: Nlrp12 and Inflammatory Disordersmentioning

confidence: 80%

Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma

Khan

Zaki

2020

IJMS

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“…Formation of NLRP12 inflammasome can activate caspase 1 [54,55], which produces interleukin and leads to cell death. But NLRP12 can also form mixed inflammasomes with other NLRPs, including NLRP3, and then play an inhibitory role [56,57]. NLRP12 is also involved in adaptative immunity and controls MHC class I expression through a yet ill-defined mechanism [58].…”

Section: Clpro Cleaves Tab1 and Nlrp12mentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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“…To date, most studies have implicated TRIM25 as a critical mediator of innate immune signalling through ubiquitination of RIG-I [2,11,[101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118], while only a handful of studies have proposed RIG-I-independent mechanisms [46,119]. Recent years have brought both exciting discoveries and rousing controversies regarding how ubiquitin and E3 ligases precisely function to activate RIG-I for antiviral signalling, with some groups suggesting a single factor operates as the critical component while others have put forth a cooperative model based on trends gleaned from numerous studies.…”

Section: Innate Antiviral Signalling Functions Of Trim25: Rig-i-depenmentioning

confidence: 99%

“…Additional evidence showing regulation of RIG-I by TRIM25 comes from studies that have uncovered several host proteins that regulate the E3 ligase activity of TRIM25 (e.g. NDR2, NLRP12, Caspase-12, Lnczc3h7a), thereby affecting downstream activation of RIG-I [103,114,[116][117][118]. Furthermore, direct interactions between endogenous TRIM25 and RIG-I have been demonstrated during viral infection [105,110].…”

Section: Innate Antiviral Signalling Functions Of Trim25: Rig-i-depenmentioning

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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NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25

Cited by 71 publications

References 53 publications

Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma

Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

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

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