Metabolic control of BRISC-SHMT2 assembly regulates immune signaling

SHMT2 regulates one-carbon transfer reactions essential for amino acid and nucleotide metabolism, using PLP as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active, tetrameric state. SHMT2 also promotes inflammatory cytokine signaling by interacting with the BRISC deubiquitylase (DUB) complex, although it is unclear if this function relates to metabolism. We reveal the cryo-EM structure of human BRISC-SHMT2 complex at 3.8 Å resolution. The BRISC complex is a U-shaped dimer of four subunits and SHMT2 sterically blocks the BRCC36 active site and inhibits DUB activity. Only the inactive SHMT2 dimer, but not the active, PLP-bound tetramer binds and inhibits BRISC. BRISC mutations that disrupt SHMT2 binding impaired type I interferon signaling in response to inflammatory stimuli. Intracellular PLP levels regulated BRISC-SHMT2 interaction and inflammatory cytokine responses. These data reveal a new mechanism of metabolite regulation of DUB activity and inflammatory signaling.