Structural and Functional Basis of JAMM Deubiquitinating Enzymes in Disease
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ABSTRACT:
SUBMITTER: Pan X
PROVIDER: S-EPMC9313428 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BRCC36 is a JAMM (JAB1/MPN/Mov34 metalloenzyme) domain, lysine 63-ubiquitin (K63-Ub)-specific deubiquitinating enzyme (DUB) and a member of two protein complexes: the DNA damage-responsive BRCA1-RAP80 complex, and the cytoplasmic BRCC36 isopeptidase complex (BRISC). The presence of several identical constituents in both complexes suggests common regulatory mechanisms and potential competition between K63-Ub-related signaling in cytoplasmic and nuclear compartments. Surprisingly, we discover that BRCC36 DUB activity requires different interactions within the context of each complex. Abraxas and BRCC45 were essential for BRCC36 DUB activity within the RAP80 complex, whereas KIAA0157/Abro was the only interaction required for DUB activity within the BRISC. Poh1 also required protein interactions for activity, suggesting a common regulatory mechanism for JAMM domain DUBs. Finally, BRISC deficiency enhanced formation of the BRCA1-RAP80 complex in vivo, increasing BRCA1 levels at DNA double strand breaks. These findings reveal that JAMM domain DUB activity and K63-Ub levels are regulated by multiple mechanisms within the cell.
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Project description:Ubiquitination is a reversible post-translational modification that plays a dynamic role in regulating most eukaryotic processes. Deubiquitinating enzymes (DUBs), which hydrolyze the isopeptide or peptide linkages joining ubiquitin to substrate lysines or N-termini, therefore play a key role in ubiquitin signaling. Cells employ multiple mechanisms to regulate DUB activity and thus ensure the appropriate biological response. Recent structural studies have shed light on several different mechanisms by which DUB activity and specificity is regulated.
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Project description:Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication.
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Project description:Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of stemness-related proteins are essential for CSC maintenance and differentiation, even leading to execute various stem cell fate choices. Deubiquitinating enzymes (DUBs), specifically disassembling ubiquitin chains, are important to maintain the balance between ubiquitination and deubiquitination. In this review, we have focused on the DUBs regulation of stem cell fate determination. For example, we discuss deubiquitinase inhibition may lead stem cell transcription factors and CSCs-related protein degradation. Also, CSCs microenvironment is regulated by DUBs activity. Our review provides a new insight into DUBs activity by emphasizing their cellular role in regulating stem cell fate and illustrates the opportunities for the application of DUBs inhibitors in the CSC-targeted therapy.
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