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Metabolic control of BRISC–SHMT2 assembly regulates immune signalling

Walden, Miriam ; Tian, Lei ; Ross, Rebecca L. ; Sykora, Upasana M. ; Byrne, Dominic P. ; Hesketh, Emma L. ; Masandi, Safi K. ; Cassel, Joel ; George, Rachel and Ault, James R. , et al. (2019) In Nature 570(7760). p.194-199
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... (More)

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.

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Nature
volume
570
issue
7760
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:31142841
  • scopus:85066815714
ISSN
0028-0836
DOI
10.1038/s41586-019-1232-1
language
English
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yes
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9fb205c9-5a5d-44e2-8437-26f6b8cda352
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2019-06-26 08:23:02
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2020-02-26 07:30:35
@article{9fb205c9-5a5d-44e2-8437-26f6b8cda352,
  abstract     = {<p>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.</p>},
  author       = {Walden, Miriam and Tian, Lei and Ross, Rebecca L. and Sykora, Upasana M. and Byrne, Dominic P. and Hesketh, Emma L. and Masandi, Safi K. and Cassel, Joel and George, Rachel and Ault, James R. and El Oualid, Farid and Pawłowski, Krzysztof and Salvino, Joseph M. and Eyers, Patrick A. and Ranson, Neil A. and Del Galdo, Francesco and Greenberg, Roger A. and Zeqiraj, Elton},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7760},
  pages        = {194--199},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Metabolic control of BRISC–SHMT2 assembly regulates immune signalling},
  url          = {http://dx.doi.org/10.1038/s41586-019-1232-1},
  doi          = {10.1038/s41586-019-1232-1},
  volume       = {570},
  year         = {2019},
}