Ubiquitination in the regulation of inflammatory cell death and cancer

Abstract

The ubiquitin system is complex, multifaceted, and is crucial for the modulation of a vast number of cellular processes. Ubiquitination is tightly regulated at different levels by a range of enzymes including E1s, E2s, and E3s, and an array of DUBs. The UPS directs protein degradation through the proteasome, and regulates a wide array of cellular processes including transcription and epigenetic factors as well as key oncoproteins. Ubiquitination is key to the dynamic regulation of programmed cell death. Notably, the TNF signaling pathway is controlled by competing ubiquitin conjugation and deubiquitination, which governs both proteasomal degradation and signaling complex formation. In the inflammatory response, ubiquitination is capable of both activating and dampening inflammasome activation through the control of either protein stability, complex formation, or, in some cases, directly affecting receptor activity. In this review, we discuss the enzymes and targets in the ubiquitin system that regulate fundamental cellular processes regulating cell death, and inflammation, as well as disease consequences resulting from their dysregulation. Finally, we highlight several pre-clinical and clinical compounds that regulate ubiquitin system enzymes, with the aim of restoring homeostasis and ameliorating diseases.

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

“…Polyubiquitination is a posttranslational modification process that plays critical role in programmed cell death or NLRP3-mediated inflammasome activation through covalent linkage of ubiquitin to lysine residues in target proteins [ 20 , 22 , 55 , 56 ]. Recent studies have demonstrated that GSDMD is essential in pyroptosis.…”

“…Posttranslational modification of inflammasome components via ubiquitin (Ub) is critical for the regulation of inflammasomes activation [ 20 , 21 ]. Ubiquitination of NLRP3, caspase-1/11, ASC, IL-1β, and other inflammasome components regulates several essential nodes in the regulatory networks [ 20 – 27 ]. E3 ubiquitin ligases such as Pellino 2 mediates K63-linked polyubiquitination and NLRP3 inflammasome activation [ 28 ].…”

Pathways of Non-enzymatic Lysine Acylation

“…However, the particularly interesting field of possible cross-talk with other lysine modifications like ubiquitylation is currently poorly understood. Enzymatic ligation of ubiquitin to proteins was originally identified as a pivotal mark for degradation by the proteasomal system ( Hershko et al, 1980 ), but nowadays ubiquitylation is also linked to distinct functions like cellular signaling and quality control of the genome ( Schwertman et al, 2016 ; Cockram et al, 2021 ). Ubiquitin is a small protein consisting of 76 amino acids and was discovered “ubiquitously” in tissues of eukaryotic organisms ( Goldstein et al, 1975 ).…”

Immunoprecipitation Strategies to Isolate RIPK1/RIPK3 Complexes in Mouse Macrophages

“…Core proteins involved in the execution of cell death, including RIPK1, RIPK3, and caspase-8, undergo multiple post-translational modifications that play key roles in the regulation of Complex II assembly and the selection of the form of cell death (Cockram et al, 2021;Delanghe, Dondelinger, & Bertrand, 2020;Oberst et al, 2010;Pop et al, 2011). These modifications, which include phosphorylations, ubiquitinations, proteolytic processing, and others, are exerted through the interactions of the core Complex II components with various factors recruited into the complex as well as those acting outside of the complex.…”