Metabolic control of BRISC–SHMT2 assembly regulates immune signalling

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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 Del Galdo
  • Roger A. Greenberg
  • Elton Zeqiraj
Enheter & grupper
Externa organisationer
  • University of Leeds
  • University of Pennsylvania
  • University of Liverpool
  • The Wistar Institute
  • Warsaw University of Life Sciences
  • UbiQ Bio BV
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biokemi och molekylärbiologi
Originalspråkengelska
Sidor (från-till)194-199
Antal sidor6
TidskriftNature
Volym570
Utgivningsnummer7760
StatusPublished - 2019
PublikationskategoriForskning
Peer review utfördJa