A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.

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.
Mesh Terms:
Animals, Female, Glycine Hydroxymethyltransferase, HEK293 Cells, HeLa Cells, Humans, Interferons, Membrane Proteins, Mice, Mice, Inbred C57BL, Multiprotein Complexes, RNA, Small Interfering, Receptor, Interferon alpha-beta, Ubiquitination, Ubiquitins
Cell Rep
Date: Oct. 17, 2013
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