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)

Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.
 ...
PMID:p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation. 2825 48

Ubiquitin (Ub) shares the highest sequence identity with neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8) in the Ub-like protein family. However, different enzyme systems are precisely employed for targeting Ub and NEDD8 to specific substrates. The molecular determinants for distinguishing between Ub and NEDD8 by Ub-specific peptidases (USPs) remain poorly characterized. By replacing the non-conserved residues of Ub with their NEDD8 equivalents by mutagenesis, and vice versa, we observed that the Ub4K, Ub12E, and Ub14E mutants partially and the Ub4K/12E/14E/72A mutant completely prevented their hydrolysis by USP2. The NEDD84F and NEDD814T mutants were slightly hydrolyzed by USP2; however, the NEDD812T/14T/72R and NEDD84F/12T/14T/72R mutants were accessible for hydrolysis by USP2, suggesting that Ub and NEDD8 residues 4, 12, 14, and 72 serve as the molecular determinants for specific recognition by USP2. We also demonstrated that the level of inhibition caused by Ub mutants with multiple mutation sites was not purely additive when compared with the single mutation results. Furthermore, USP2 was determined to bind to the N-terminus of Ub to form a stable interaction, after which it binds with the C-terminus of Ub to ensure substrate specificity. The same results were also discovered when Ub, Ub4K/12E/14E/72A, NEDD8, and NEDD84F/12T/14T/72R were incubated with USP21.
 ...
PMID:The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2. 2853 28

RIG-I and MDA5 are cytoplasmic viral RNA sensors and are essential for antiviral innate immune responses, such as type I interferon production. Post-translational modification is critical for the activation and inactivation of RIG-I and MDA5. At least seven ubiquitin ligases have been reported to be involved in either K63- or K48-linked polyubiquitination of RIG-I and MDA5, and these ubiquitin ligases are further regulated by other factors. TRIM25 is an E3 ubiquitin ligase that delivers a K63-linked polyubiquitin moiety to the caspase activation and recruitment domains (CARDs) of RIG-I, thereby activating the antiviral innate immune response. Recent studies have shown that NDR2, ZCCHC3, and Lnczc3h7a promote TRIM25-mediated RIG-I activation. Riplet is another ubiquitin ligase that mediates the K63-linked polyubiquitination of the C-terminal domain (CTD) of RIG-I; however, it was also reported that Riplet delivers the K63-linked polyubiquitin moiety to the CARDs of RIG-I as well as to the CTD, thereby activating RIG-I. Further, there are several factors that attenuate the activation of RIG-I and MDA5. RNF125, TRIM40, and c-Cbl mediate K48-linked polyubiquitination and induce degradation of RIG-I and/or MDA5. USP21 and CYLD remove the K63-linked polyubiquitin chain from RIG-I, and NLRP12 inhibits polyubiquitin-mediated RIG-I activation. Although these new regulators have been reported, their distinctive roles and functional differences remain elusive, and in some cases, studies on the topic are contradictory to each other. In the present review, recent studies related to post-translational modifications of RIG-I and MDA5 are summarized, and several controversies and unanswered questions in this field are discussed.
 ...
PMID:Recent Advances and Contradictions in the Study of the Individual Roles of Ubiquitin Ligases That Regulate RIG-I-Like Receptor-Mediated Antiviral Innate Immune Responses. 3267 Feb 86