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Nature. 2019 Jun;570(7760):194-199. doi: 10.1038/s41586-019-1232-1. Epub 2019 May 29.

Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.

Author information

1
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
2
Department of Cancer Biology, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR Biomedical Research Centre, University of Leeds, Leeds, UK.
4
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
5
The Wistar Cancer Center for Molecular Screening, The Wistar Institute, Philadelphia, PA, USA.
6
UbiQ Bio BV, Amsterdam, The Netherlands.
7
Warsaw University of Life Sciences, Warsaw, Poland.
8
Department of Translational Medicine, Clinical Sciences, Lund University, Lund, Sweden.
9
Department of Cancer Biology, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rogergr@pennmedicine.upenn.edu.
10
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK. e.zeqiraj@leeds.ac.uk.

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.

PMID:
31142841
DOI:
10.1038/s41586-019-1232-1

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