Dataset Information

The protease calpain2a limits innate immunity by targeting TRAF6 in teleost fish.

ABSTRACT: TNF receptor-associated factor 6 (TRAF6) plays a key signal transduction role in both antibacterial and antiviral signaling pathways. However, the regulatory mechanisms of TRAF6 in lower vertebrates are less reported. In this study, we identify calpain2a, is a member of the calcium-dependent proteases family with unique hydrolytic enzyme activity, functions as a key regulator for antibacterial and antiviral immunity in teleost fish. Upon lipopolysaccharide (LPS) stimulation, knockdown of calpain2a promotes the upregulation of inflammatory cytokines. Mechanistically, calpain2a interacts with TRAF6 and reduces the protein level of TRAF6 by hydrolyzing. After loss of enzymatic activity, mutant calpain2a competitively inhibits dimer formation and auto-ubiquitination of TRAF6. Knockdown of calpain2a also promotes cellular antiviral response. Mutant calpain2a lacking hydrolase activity represses ubiquitination of IFN regulatory factor (IRF) 3/7 from TRAF6. Taken together, these findings classify calpain2a is a negative regulator of innate immune responses by targeting TRAF6 in teleost fish.

SUBMITTER: Chen Y

PROVIDER: S-EPMC10066338 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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The protease calpain2a limits innate immunity by targeting TRAF6 in teleost fish.

Chen Yang Y Wang Pengfei P Li Qi Q Yan Xiaolong X Xu Tianjun T

Communications biology 20230331 1

TNF receptor-associated factor 6 (TRAF6) plays a key signal transduction role in both antibacterial and antiviral signaling pathways. However, the regulatory mechanisms of TRAF6 in lower vertebrates are less reported. In this study, we identify calpain2a, is a member of the calcium-dependent proteases family with unique hydrolytic enzyme activity, functions as a key regulator for antibacterial and antiviral immunity in teleost fish. Upon lipopolysaccharide (LPS) stimulation, knockdown of calpain ...[more]

PMID: 37002312

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Project description:Ubiquitination, as one of the most prevalent posttranslational modifications of proteins, enables a tight control of host immune responses. Many viruses hijack the host ubiquitin system to regulate host antiviral responses for their survival. Here, we found that the fish pathogen nervous necrosis virus (NNV) recruited Lateolabrax japonicus E3 ubiquitin ligase ring finger protein 34 (LjRNF34) to inhibit the RIG-I-like receptor (RLR)-mediated interferon (IFN) response via ubiquitinating Lateolabrax japonicus TANK-binding kinase 1 (LjTBK1) and interferon regulatory factor 3 (LjIRF3). Ectopic expression of LjRNF34 greatly enhanced NNV replication and prevented IFN production, while deficiency of LjRNF34 led to the opposite effect. Furthermore, LjRNF34 targeted LjTBK1 and LjIRF3 via its RING domain. Of note, the interactions between LjRNF34 and LjTBK1 or LjIRF3 were conserved in different cellular models derived from fish. Mechanically, LjRNF34 promoted K27- and K48-linked ubiquitination and degradation of LjTBK1 and LjIRF3, which in turn diminished LjTBK1-induced translocation of LjIRF3 from the cytoplasm to the nucleus. Ultimately, NNV capsid protein (CP) was found to bind with LjRNF34, CP induced LjTBK1 and LjIRF3 degradation, and IFN suppression depended on LjRNF34. Our finding demonstrates a novel mechanism by which NNV CP evaded host innate immunity via LjRNF34 and provides a potential drug target for the control of NNV infection. IMPORTANCE Ubiquitination plays an essential role in the regulation of innate immune responses to pathogens. NNV, a type of RNA virus, is the causal agent of a highly destructive disease in a variety of marine and freshwater fish. A previous study reported NNV could hijack the ubiquitin system to manipulate the host's immune responses; however, how NNV utilizes ubiquitination to facilitate its own replication is not well understood. Here, we identified a novel distinct role of E3 ubiquitin ligase LjRNF34 as an IFN antagonist to promote NNV infection. NNV capsid protein utilized LjRNF34 to target LjTBK1 and LjIRF3 for K27- and K48-linked ubiquitination and degradation. Importantly, the interactions between LjRNF34 and CP, LjTBK1, or LjIRF3 are conserved in different cellular models derived from fish, suggesting it is a general immune evasion strategy exploited by NNV to target the IFN response via RNF34.

Dataset Information

The protease calpain2a limits innate immunity by targeting TRAF6 in teleost fish.

Publications

The protease calpain2a limits innate immunity by targeting TRAF6 in teleost fish.

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