K63 ubiquitination in immune signaling

Abstract

Ubc13-catalyzed K63 ubiquitination is a major control point for immune signaling. Recent evidence has shown that the control of multiple immune functions, including chronic inflammation, pathogen responses, lymphocyte activation, and regulatory signaling, is altered by K63 ubiquitination. In this review, we detail the novel cellular sensors that are dependent on K63 ubiquitination for their function in the immune signaling network. Many pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can target K63 ubiquitination to inhibit pathogen immune responses; we describe novel details of the pathways involved and summarize recent clinically relevant SARS-CoV-2-specific responses. We also discuss recent evidence that regulatory T cell (Treg) versus T helper (T H ) 1 and T H 17 cell subset regulation might involve K63 ubiquitination. Knowledge gaps that merit future investigation and clinically relevant pathways are also addressed.

Proteolysis dysfunction in the process of aging and age-related diseases

“…Polyubiquitination through K48 of ubiquitin leads to proteasomal degradation, and K63-linked ubiquitin plays a role in signaling, endocytosis, or even regulating kinase activation ( Sadowski and Sarcevic, 2010 ). It was demonstrated that ubiquitination via K63 is important for the regulation of signal transduction by multiple receptors of both innate and adaptive immunity, including the TLRs, NLRs, TNFR, T- and B-cell antigen receptors and many other ( Madiraju et al, 2022 ).…”

MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer

“…So far, the most thoroughly characterized polyubiquitin processes are lysine 48 (K48)-and K63-linked ubiquitination. K48-linked chains prefer to target proteins for proteasomal degradation, while K63-linked chains act as a molecular glue for complex formation in various signaling pathways and also participate in protein degradation (Grice & Nathan, 2016; Hayden & Ghosh, 2008; Liu et al, 2018; Madiraju et al, 2022; Wang et al, 2022). We next examined which sites of polyubiquitin chains attached to ERα could be removed by MYSM1.…”

“…MYSM1 belongs to the JAMM family of deubiquitinase, so we hypothesized it may participate in maintenance of ERα stability through its deubiquitinase activity. Next, we turned to perform western blot to detect the effect of full length of MYSM1 to target proteins for proteasomal degradation, while K63-linked chains act as a molecular glue for complex formation in various signaling pathways and also participate in protein degradation (Grice & Nathan, 2016;Hayden & Ghosh, 2008;Liu et al, 2018;Madiraju et al, 2022;Wang et al, 2022). We next examined which sites of polyubiquitin chains attached to ERα could be removed by MYSM1.…”

Novel Lactams as Cbl-b Inhibitors for Treating Cancer

“…The table below shows representative compounds tested for Cbl-b inhibition and the biological data obtained from testing representative examples. − …”