Deubiquitylating Enzymes in Cancer and Immunity

Abstract

Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post‐translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein–protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs’ functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus‐faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi‐faced roles of DUBs in cancer and immunity.

Ubiquitous regulation of cerebrovascular diseases by ubiquitin‐modifying enzymes

“… 156 , 157 In the past two decades, DUBs have emerged as novel drug targets for cancer and immune disorders. 158 In the foreseen future, UME inhibitors, particularly DUB inhibitors, may also enrich the therapeutic armamentarium for CVDs. Notably, in the NF‐κB signaling, which critically regulates inflammation and cell death in multiple CVDs, stimulus‐specific polyubiquitin scaffolds provide the docking sites for key upstream signaling molecules including IKKs.…”

Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases

“…Ubiquitination is a reversible process that is accomplished by deubiquitinases (DUBs). The approximately 100 DUBs in the human body are categorized into nine families [ 8 ]: ubiquitin‐specific proteases (USPs), ovarian tumor proteases (OTUs), ubiquitin C‐terminal hydrolases (UCHs), Machado‐Joseph domain‐containing proteases (MJDs, also known as Josephins), JAMM/MPN domain‐associated Zn‐depend metalloproteases (JAMMs, also known as MPN+), the motif interacting with ubiquitin (MIU)‐containing novel DUB family (MINDYs), monocyte chemotactic protein‐induced proteins (MCPIPs), permuted papain fold peptidases of dsRNA viruses and eukaryotes (PPPDEs), and zinc finger (ZnF) containing ubiquitin peptidase 1 (ZUP1) [ 9 ]. A burgeoning volume of researches has demonstrated that dysregulation of the balance between ubiquitination and deubiquitination can lead to a wide variety of adverse consequences [ 10 ].…”

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

“…Ubiquitination is a dynamic and reversible process, with deubiquitinating enzymes (DUBs) able to reverse the ubiquitination of proteins ( 51 ). This process, known as deubiquitination, is essential for maintaining the balance and regulation of protein ubiquitination within the cell, impacting various cellular processes and homeostasis ( 52 , 53 ).…”