Metabolic control of BRISC–SHMT2 assembly regulates immune signalling

Miriam Walden, Lei Tian, Rebecca L. Ross, Upasana M. Sykora, Dominic P. Byrne, Emma L. Hesketh, Safi K. Masandi, Joel Cassel, Rachel George, James R. Ault, Farid El Oualid, Krzysztof Pawłowski, Joseph M. Salvino, Patrick A. Eyers, Neil A. Ranson, Francesco Galdo, Roger A. Greenberg () and Elton Zeqiraj ()
Additional contact information
Miriam Walden: University of Leeds
Lei Tian: University of Pennsylvania
Rebecca L. Ross: University of Leeds
Upasana M. Sykora: University of Leeds
Dominic P. Byrne: University of Liverpool
Emma L. Hesketh: University of Leeds
Safi K. Masandi: University of Leeds
Joel Cassel: The Wistar Institute
Rachel George: University of Leeds
James R. Ault: University of Leeds
Farid El Oualid: UbiQ Bio BV
Krzysztof Pawłowski: Warsaw University of Life Sciences
Joseph M. Salvino: The Wistar Institute
Patrick A. Eyers: University of Liverpool
Neil A. Ranson: University of Leeds
Francesco Galdo: University of Leeds
Roger A. Greenberg: University of Pennsylvania
Elton Zeqiraj: University of Leeds

Nature, 2019, vol. 570, issue 7760, 194-199

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1232-1

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