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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Female
  • Glycine Hydroxymethyltransferase / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferons / genetics
  • Interferons / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism*
  • Ubiquitination
  • Ubiquitins / metabolism

Substances

  • Membrane Proteins
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Ubiquitins
  • Receptor, Interferon alpha-beta
  • Interferons
  • Glycine Hydroxymethyltransferase