October 5, 2021—Ubiquitin is a post-translational modification to proteins that has many cellular functions, including the regulation of inflammatory signalling and innate immune responses. Innate immune receptors on the cell surface recognize specific infectious agents and cytokines. In response to these external cues, chains of ubiquitin molecules are added to the receptors by enzymes called ubiquitin ligases to activate intracellular signaling and various self-defense processes.
This stimulation is balanced by removal of ubiquitin by deubiquitinases. The importance of tight control of ubiquitin linkages is demonstrated by altered deubiquitinase activity leading to inflammatory immune disorders and cancers. While the role of deubiquitinases in moderating inflammation is becoming clearer, we are only beginning to understand the complexities of the regulation of deubiquitinases themselves.
Ludwig Oxford’s Mads Gyrd-Hansen and collaborators from the Department of Biochemistry, Oxford, MRC Laboratory of Molecular biology, Cambridge, and the University of Melbourne set out to investigate the regulation of the deubiquitinase CYLD, a tumour suppressor important for skin homeostasis. The team reported in the journal Cell Reports that two regions outside CYLD’s catalytic domain contribute to CYLD regulation. Called CAP-Gly2 and CAP-Gly3, these regions are novel ubiquitin-binding domains and CAP-Gly3 is required for full CYLD deubiquitinase activity in vitro and for regulation of immune receptor signalling. In addition, they discovered a previously unknown site where CYLD is modified by phosphorylation. This phosphorylation stimulates CYLD to select a specific type of ubiquitin linkage for cleavage.