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The Roles of TRAF3 in Immune Responses.

ABSTRACT: Seven tumor necrosis factor receptor- (TNFR-) associated factors (TRAFs) have been found in mammals, which are primarily involved in the signal translation of the TNFR superfamily, the Toll-like receptor (TLR) family, and the retinoic acid-inducible gene I- (RIG-I-) like receptor (RLR) family. TRAF3 is one of the most diverse members of the TRAF family. It can positively regulate type I interferon production while negatively regulating signaling pathways of classical nuclear factor-κB, nonclassical nuclear factor-κB, and mitogen-activated protein kinase (MAPK). This review summarizes the roles of TRAF3 signaling and the related immune receptors (e.g., TLRs) in several preclinical and clinical diseases and focuses on the roles of TRAF3 in immune responses, the regulatory mechanisms, and its role in disease.

SUBMITTER: Lin M

PROVIDER: S-EPMC9949957 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The Roles of TRAF3 in Immune Responses.

Lin Mengjiao M Ji Xiaoli X Lv Yan Y Cui Dawei D Xie Jue J

Disease markers 20230216

Seven tumor necrosis factor receptor- (TNFR-) associated factors (TRAFs) have been found in mammals, which are primarily involved in the signal translation of the TNFR superfamily, the Toll-like receptor (TLR) family, and the retinoic acid-inducible gene I- (RIG-I-) like receptor (RLR) family. TRAF3 is one of the most diverse members of the TRAF family. It can positively regulate type I interferon production while negatively regulating signaling pathways of classical nuclear factor-<i>κ</i>B, no ...[more]

PMID: 36845015

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Project description:Human enterovirus D68 (EV-D68) has received considerable attention recently as a global reemergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis (AFM). The nonstructural protein 2A protease (2Apro) of EVs, which functions in the cleavage of host proteins, comprises a pivotal part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. In this study, we found that EV-D68 inhibited antiviral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3), which is the key factor for type I interferon production. EV-D68 inhibited Sendai virus (SEV)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression in HeLa and HEK293T cells. Furthermore, we demonstrated that EV-D68 and 2Apro were able to cleave the C-terminal region of TRAF3 in HeLa and HEK293T cells, respectively. A cysteine-to-alanine substitution at amino acid 107 (C107A) in the 2Apro protease resulted in the loss of cleavage activity to TRAF3, and mutation of glycine at amino acid 462 to alanine (G462A) in TRAF3 conferred resistance to 2Apro These results suggest that control of TRAF3 by 2Apro may be a mechanism EV-D68 utilizes to subvert host innate immune responses.IMPORTANCE Human enterovirus 68 (EV-D68) has received considerable attention recently as a global reemergent pathogen because it causes severe respiratory tract infections and acute flaccid myelitis. The nonstructural protein 2A protease (2Apro) of EV, which functions in cleavage of host proteins, comprises an essential part of the viral immune evasion process. However, the pathogenic mechanism of EV-D68 is not fully understood. Here, we show for the first time that EV-D68 inhibited antiviral type I interferon responses by cleaving tumor necrosis factor receptor-associated factor 3 (TRAF3). Furthermore, we identified the key cleavage site in TRAF3. Our study may suggest a new mechanism by which the 2Apro of EV facilitates subversion of host innate immune responses. These findings increase our understanding of EV-D68 infection and may help identify new antiviral targets against EV-D68.

Dataset Information

The Roles of TRAF3 in Immune Responses.

Publications

The Roles of TRAF3 in Immune Responses.

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