1. Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.
- Author
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Walden M, Tian L, Ross RL, Sykora UM, Byrne DP, Hesketh EL, Masandi SK, Cassel J, George R, Ault JR, El Oualid F, Pawłowski K, Salvino JM, Eyers PA, Ranson NA, Del Galdo F, Greenberg RA, and Zeqiraj E
- Subjects
- Cryoelectron Microscopy, Deubiquitinating Enzymes antagonists & inhibitors, Deubiquitinating Enzymes chemistry, Deubiquitinating Enzymes ultrastructure, Glycine Hydroxymethyltransferase ultrastructure, HEK293 Cells, Humans, Inflammation immunology, Models, Molecular, Multienzyme Complexes chemistry, Multienzyme Complexes genetics, Mutation, Protein Binding, Protein Multimerization, Protein Structure, Quaternary, Pyridoxal Phosphate metabolism, Deubiquitinating Enzymes metabolism, Glycine Hydroxymethyltransferase metabolism, Interferon Type I immunology, Multienzyme Complexes immunology, Multienzyme Complexes metabolism, Signal Transduction immunology
- Abstract
Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (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 signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 Å. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.
- Published
- 2019
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