| First Author | Zheng H | Year | 2013 |
| Journal | Cell Rep | Volume | 5 |
| Issue | 1 | Pages | 180-93 |
| PubMed ID | 24075985 | Mgi Jnum | J:203788 |
| Mgi Id | MGI:5528747 | Doi | 10.1016/j.celrep.2013.08.025 |
| Citation | Zheng H, et al. (2013) A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep 5(1):180-93 |
| abstractText | 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. |
