Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

Abstract

Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies.

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

“…A number of E3 ligases have been discovered to regulate NLRP3 inflammasome by conjugating ubiquitin chains onto NLRP3, ASC, caspase‐1, or upstream regulators (Lopez‐Castejon & Edelmann, ). The E3‐mediated ubiquitination of NLRP3 inflammasome can be reversed by DUBs, but less is known about the DUBs that are involved in this process.…”

“…Our data demonstrate a dynamic interplay between the centrosome and inflammasome and provide valuable insight into the molecular mechanism of the NEK7-mediated NLRP3 inflammasome activation. A number of E3 ligases have been discovered to regulate NLRP3 inflammasome by conjugating ubiquitin chains onto NLRP3, ASC, caspase-1, or upstream regulators (Lopez-Castejon & Edelmann, 2016). The E3-mediated ubiquitination of NLRP3 inflammasome can be reversed by DUBs, but less is known about the DUBs that are involved in this process.…”

Structure and Function of Viral Deubiquitinating Enzymes

“…Additionally, A20 can also bind to specific E2 enzymes and induce their degradation as a mechanism to prevent ubiquitination of other proteins [54]. Several more DUBs that play a role in the regulation of the immune response have been identified such as OTU DUBs Cezanne, OTULIN, and UPS DUBs USP3, 13, and 21 [7,[55][56][57][58]. Mutations in genes encoding DUBs involved in negative regulation of innate immune signaling, like CYLD and A20, can lead to the development of diseases including cancer and autoimmune and inflammatory disorders, highlighting the importance of DUB-controlled immune signaling [59,60].…”

USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

“…USP2a , USP10 , and USP20 regulate immune response through targeting TRAF6. USP4 and USP18 target TAK1, USP25 targets TRAF3, A20 and OTULIN could target RIPK1/2 . In antiviral immune response, RIG‐I, which mediated type I IFN production, is undependable for controlling virus propagation.…”