Metabolic control of BRISC-SHMT2 assembly regulates immune signalling
Open accessAbstract
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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SHMT2 has a novel function that contributes to immune regulation through the BRISC complex.
“Recent structural studies have identified a novel function of SHMT2 that contributes to immune regulation through the BRISC complex.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [129]
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A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight
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- Authors
- Walden, M., Tian, L., Ross, R. L., Sykora, U. M., Byrne, D. P., Hesketh, E. L., Masandi, S. K., Cassel, J., George, R., Ault, J. R., El Oualid, F., Pawłowski, K., Salvino, J. M., Eyers, P. A., Ranson, N. A., Del Galdo, F., Greenberg, R. A., & Zeqiraj, E.
- Affiliations
- University of Leeds (GB)
- University of Pennsylvania (US)
- University of Liverpool (GB)
- The Wistar Institute (US)
- Warsaw University of Life Sciences (PL)
- Corresponding author
- Greenberg, Roger A.
- Zeqiraj, Elton
- ORCID
- Venue
- Nature
- Published
- 2019-05-29
- Volume
- 570
- Issue
- 7760
- Pages
- 194-199
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6914362
- OpenAlex
- W2947028185
- Cited by
- 85
- References
- 48
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 8 · 2023: 5 · 2022: 9 · 2021: 18 · 2020: 13 · 2019: 2
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Wellcome Trust (108466, 108466/Z/15/Z, 200523, 200523/Z/16/Z, 208385/Z/17/Z)
- Kennedy Trust for Rheumatology Research (KENN171801)
- National Institute for Health and Care Research (CDF-2014-07-051)
- Medical Research Council (MC_PC_16050)
- Biotechnology and Biological Sciences Research Council (BB/N021703/1, BB/L021250/1, BB/S018514/1, BB/E012558/1)
- National Cancer Institute (R01CA138835, P30CA010815)
- National Institute of General Medical Sciences (R01GM101149)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- SHMT2, pyridoxal phosphate, BRCC36, one-carbon metabolism, protein complex structure, type I interferon signaling, protein dimerization
- MeSH terms
- Deubiquitinating Enzymes, Humans, Inflammation, Interferon Type I, Models, Molecular, Multienzyme Complexes, Mutation, Protein Binding, Pyridoxal Phosphate, Glycine Hydroxymethyltransferase, Signal Transduction, Cryoelectron Microscopy, Protein Structure, Quaternary, Protein Multimerization, HEK293 Cells
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