Lysine63-linked ubiquitin (K63-Ub) chains represent a particular ubiquitin topology that mediates proteasome-independent signaling events.The deubiquitinating enzyme (DUB) BRCC36 segregates into distinct nuclear and cytoplasmic complexes that are specific for K63-Ub Queen Lifestyle Adjustable Bed hydrolysis.RAP80 targets the five-member nuclear BRCC36 complex to K63-Ub chains at DNA double-strand breaks.The alternative four-member BRCC36 containing complex (BRISC) lacks a known targeting moiety.
Here, we identify serine hydroxymethyltransferase (SHMT) as a previously unappreciated component that fulfills this function.SHMT directs BRISC activity at K63-Ub chains conjugated to the type 1 interferon (IFN) receptor chain 1 (IFNAR1).BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, thus limiting its K63-Ub-mediated internalization and lysosomal degradation.BRISC-deficient cells and mice exhibit attenuated responses to IFN and are protected from IFN-associated immunopathology.
These studies reveal a mechanism of DUB regulation and suggest a therapeutic Hockey Protective - Gloves - Junior use of BRISC inhibitors for treating pathophysiological processes driven by elevated IFN responses.