A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses
Hui Zheng,
Vibhor Gupta,
Jeffrey Patterson-Fortin,
Sabyasachi Bhattacharya,
Kanstantsin Katlinski,
Junmin Wu,
Bentley Varghese,
Christopher J. Carbone,
Bernadette Aressy,
Serge Y. Fuchs,
Roger A. Greenberg
Affiliations
Hui Zheng
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
Vibhor Gupta
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Jeffrey Patterson-Fortin
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sabyasachi Bhattacharya
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
Kanstantsin Katlinski
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
Junmin Wu
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Bentley Varghese
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
Christopher J. Carbone
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
Bernadette Aressy
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Serge Y. Fuchs
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
Roger A. Greenberg
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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.
