A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses

Abstract

SUMMARY 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 heretofore-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 novel mechanism of DUB regulation, and suggest a therapeutic use of BRISC inhibitors for treating pathophysiologic processes driven by elevated IFN responses.

Mechanisms of regulation and diversification of deubiquitylating enzyme function

“…Importantly, incorporation of BRCC36 into these two distinct complexes defines its intracellular localization and biological function. As a result, ARISC-incorporated BRCC36 functions in DNA damage repair (Shao et al, 2009) lysosomal degradation (Zheng et al, 2013), and affects mitotic spindle assembly by deubiquitylating nuclear mitotic apparatus protein 1 (NuMA1) (Yan et al, 2015). The Spt-Ada-Gcn5-acetyl transferase (SAGA) complex is another multisubunit assembly that ensures the correct localization and substrate recognition by a DUB, in this case USP22.…”

MERIT40 deficiency expands hematopoietic stem cell pools by regulating thrombopoietin receptor signaling

“…We recently reported that one of the M40-associated complexes, BRISC, localizes to and deubiquitinates actively engaged interferon receptor, thus limiting its K63-Ub-mediated internalization. 20 However, we failed to detect any changes in cell surface expression or endocytosis of the Mpl receptor in M40 null HSPCs (data not shown). Future investigation is warranted to pinpoint the exact targets of the M40 complex in HSCs.…”

“…17 The BRISC DUB complex specifically hydrolyzes lysine 63-ubiquitin (K63-Ub) conjugates, a nondegradative form of Ub that has been implicated in hematopoiesis and cytokine receptor signaling. [18][19][20] There are 8 different possible linkages for Ub chains. K48-Ub is the canonical form that targets proteins for degradation through the proteasome.…”

“…28 The BRISC complex has recently been implicated in inflammatory cytokine signaling 20 ; however, a role for BRISC in hematopoiesis has not been reported. BRISC is composed of the enzyme BRCC36 and 3 core complex constituents (KIAA0157, MERIT40 [Mediator of RAP80 Interactions and Targeting 40 kDa (M40)], and BRCC45).…”

Role of Deubiquitinating Enzymes in DNA Repair

“…A role for BRCC36 in DSB repair was initially suggested by localization studies that found BRCC36 in nuclear foci at DSB sites (or IRIF) and that the localization was dependent on RAP80 (30). Further studies found that BRCC36 forms two distinct subcomplexes: (i) a nuclear "BRCA1-A" complex, which contains BRCC36, BRCA1, BARD1, RAP80, NBA1/MERIT40, BRE/BRCC45, and CCDC98/ Abraxas (55)(56)(57)(58)(59)(60), and (ii) the cytoplasmic BRISC (BRCC36 isopeptidase complex) complex, which contains BRCC36, KIAA0157/Abro, BRE/BRCC45, and MERIT40/NBA1 (61). A key role of the BRCA1-A complex is to target or sequester BRCA1 to DSB sites to facilitate DNA repair and to regulate the cell cycle checkpoint (30)(31)(32).…”