Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The caspase recruitment domain (CARD) of intracellular adaptors and sensors plays a critical role in the assembly of signaling complexes involved in innate host defense against pathogens and in the regulation of inflammatory responses. The cytosolic receptor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA in a 5'-triphosphate-dependent manner and initiates an antiviral signaling cascade. Upon viral infection, the N-terminal CARDs of RIG-I undergo the K(63)-linked ubiquitination induced by tripartite motif protein 25 (TRIM25), critical for the interaction of RIG-I with its downstream signaling partner MAVS/VISA/IPS-1/Cardif. Here, we demonstrate the distinct roles of RIG-I first and second CARD in TRIM25-mediated RIG-I ubiquitination: TRIM25 binds the RIG-I first CARD and subsequently ubiquitinates its second CARD. The T(55)I mutation in RIG-I first CARD abolishes TRIM25 interaction, whereas the K(172)R mutation in the second CARD eliminates polyubiquitin attachment. The necessity of the intact tandem CARD for RIG-I function is further evidenced by a RIG-I splice variant (SV) whose expression is robustly up-regulated upon viral infection. The RIG-I SV carries a short deletion (amino acids 36-80) within the first CARD and thereby loses TRIM25 binding, CARD ubiquitination, and downstream signaling ability. Furthermore, because of its robust inhibition of virus-induced RIG-I multimerization and RIG-I-MAVS signaling complex formation, this SV effectively suppresses the RIG-I-mediated IFN-beta production. This study not only elucidates the vital role of the intact tandem CARD for TRIM25-mediated RIG-I activation but also identifies the RIG-I SV as an off-switch regulator of its own signaling pathway.
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PMID:Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction. 1894 94

Ubiquitin-like protein ISG15, which is robustly induced by IFN or virus, is implicated to inhibit influenza A virus (IAV) in vivo. But the underlying mechanism still remains largely unknown. In this study, we report that Herc5 could catalyze conjugation of ISG15 onto IAV-NS1 protein, the critical virulence factor of IAV. This modification produces two more species, respectively mapped to IAV-NS1 at lysine 20, 41, 217, 219, and 108, 110, and 126. The ISGylated IAV-NS1 fails to form homodimers and inhibits relevant antiviral processes. Knockdown of Herc5 or ISG15 could partially alleviate IFN-beta-induced antiviral activities against IAV, whereas ectopic expression of the Herc5-mediated ISGylation system could distinctly potentiate IFN-beta-induced antiviral effects against IAV. Notably, IAV-NS1s of H5N1 avian IAVs display less ISGylation species than that of IAV-PR8/34 (human H1N1). Consistently, IAV-PR8/34 mutants deprived of IAV-NS1's ISGylation exhibit augmented viral propagation and virulence in both cultured cells and mice. Our study reports the first microbial target of ISGylation and uncovers the direct antiviral function and mechanism of this novel modification.
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PMID:Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 protein. 2038 78