Ubiquitin-dependent and -independent functions of OTULIN in cell fate control and beyond

Abstract

Ubiquitination, and its control by deubiquitinating enzymes (DUBs), mediates protein stability, function, signaling and cell fate. The ovarian tumor (OTU) family DUB OTULIN (FAM105B) exclusively cleaves linear (Met1-linked) poly-ubiquitin chains and plays important roles in auto-immunity, inflammation and infection. OTULIN regulates Met1-linked ubiquitination downstream of tumor necrosis factor receptor 1 (TNFR1), toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) receptor activation and interacts with the Met1 ubiquitin-specific linear ubiquitin chain assembly complex (LUBAC) E3 ligase. However, despite extensive research efforts, the receptor and cytosolic roles of OTULIN and the distributions of multiple Met1 ubiquitin-associated E3-DUB complexes in the regulation of cell fate still remain controversial and unclear. Apart from that, novel ubiquitin-independent OTULIN functions have emerged highlighting an even more complex role of OTULIN in cellular homeostasis. For example, OTULIN interferes with endosome-to-plasma membrane trafficking and the OTULIN-related pseudo-DUB OTULINL (FAM105A) resides at the endoplasmic reticulum (ER). Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin-dependent and -independent functions.

Comprehensive Analysis of E3 Ubiquitin Ligases Reveals Ring Finger Protein 223 as a Novel Oncogene Activated by KLF4 in Pancreatic Cancer

“…Moreover, we are conducting additional assays to reveal the role of RNF223 in PC, including the clinical significance of RNF223 in our collected PC samples, in vivo xenograft animal assays, and immunoprecipitation-coupled MS to identify targets of RNF223 in PC. In addition, as E3 ligases have been shown to function in both ubiquitin–proteasome-dependent and ubiquitin–proteasome-independent diseases ( Cadena et al, 2019 ; Weinelt and van Wijk, 2021 ), the specific mechanism of RNF223 in PC remains to be uncovered in the future.…”

Molecular Mechanisms of DUBs Regulation in Signaling and Disease

“…The Glu16 side chain of the proximal ubiquitin is inserted into the active site, replacing the position of Asp336, and further restricting the His339 conformation [154]. Glu16 and Asp336 prompts His339 into an active conformation to further deprotonates Cys129 [156]. At the same time, Glu16 cooperates with Asn341 to further increase the catalytic activity of the catalytic center.…”

“…OTULIN deficiency results in severe auto-inflammatory disease in patients [157]. OTULIN can protect the liver against cell death and cancer, OTULIN deficiency in non-hematopoietic cells causing liver pathology [156,158]. OTULIN inhibits liver inflammation and hepatocellular carcinoma via restraining FADD-and RIPK1 kinase-mediated hepatocyte apoptosis [159].…”

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

“…OTULIN, which contains an OTU domain, exclusively cleaves M1-linked polyubiquitin chains. Structural studies have revealed that only the M1-linked polyubiquitin chain can exhibit optimal orientation in the catalytic triad of OTULIN [ 217 ]. OTULIN is related to inflammatory disease, which is known as OTULIN-related auto-inflammatory syndrome (ORAS).…”