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.
Department of Animal Biology and Mari Lowe Comparative Oncology Center, School of Veterinary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hui
H
Zheng
Vibhor
V
Gupta
Jeffrey
J
Patterson-Fortin
Sabyasachi
S
Bhattacharya
Kanstantsin
K
Katlinski
Junmin
J
Wu
Bentley
B
Varghese
Christopher J
CJ
Carbone
Bernadette
B
Aressy
Serge Y
SY
Fuchs
Roger A
RA
Greenberg
D000818:Animals; D005260:Female; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
D008565:Membrane Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D014452:Ubiquitins; D053633:Receptor, Interferon alpha-beta; D007372:Interferons; D012696:Glycine Hydroxymethyltransferase