A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.
Article Details
- CitationCopy to clipboard
Zheng H, Gupta V, Patterson-Fortin J, Bhattacharya S, Katlinski K, Wu J, Varghese B, Carbone CJ, Aressy B, Fuchs SY, Greenberg RA
A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.
Cell Rep. 2013 Oct 17;5(1):180-93. doi: 10.1016/j.celrep.2013.08.025. Epub 2013 Sep 26.
- PubMed ID
- 24075985 [ View in PubMed]
- Abstract
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 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 use of BRISC inhibitors for treating pathophysiological processes driven by elevated IFN responses.