@article{3bf9e5f276aa49ec970cdf8eb92e2153,
title = "Metabolic control of BRISC–SHMT2 assembly regulates immune signalling",
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 {\AA}. 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.",
author = "Miriam Walden and Lei Tian and Ross, {Rebecca L.} and Sykora, {Upasana M.} and Byrne, {Dominic P.} and Hesketh, {Emma L.} and Masandi, {Safi K.} and Joel Cassel and Rachel George and Ault, {James R.} and {El Oualid}, Farid and Krzysztof Paw{\l}owski and Salvino, {Joseph M.} and Eyers, {Patrick A.} and Ranson, {Neil A.} and {Del Galdo}, Francesco and Greenberg, {Roger A.} and Elton Zeqiraj",
note = "Funding Information: Acknowledgements We thank F. Sicheri, J. Fontana, A. Berry, C. Simon, I. Nissim, F. Sobott, J. Cockburn and A. Moloney for useful discussions, and R. Thompson, A. Gordon, M. Iadanza and M. Fuller for technical support. This work was supported by a Sir Henry Dale Fellowship (Wellcome Trust and the Royal Society; 200523/Z/16/Z) to E.Z., MRC MC_PC-16050 grant to E.Z. and F.D.G., NIH R01 CA138835 and a Lupus Research Alliance Target Identification in Lupus grant to R.A.G. and J.M.S., a BBSRC (BB/L021250/1) grant to N.A.R., a BBSRC TDRF grant BB/N021703/1 and North West Cancer Research grants CR1088, CR1097 to P.A.E., and a Polish National Science Centre grant (2014/15/B/NZ1/03359) to K.P. The University of Leeds mass spectrometry facility is supported by BBSRC (BB/E012558/1) and Wellcome Trust (208385/Z/17/Z) grants. The Astbury cryo-EM facility is funded by a University of Leeds ABSL award and Wellcome Trust grant 108466/Z/15/Z. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = jun,
day = "13",
doi = "10.1038/s41586-019-1232-1",
language = "English (US)",
volume = "570",
pages = "194--199",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7760",
}