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A druggable redox switch on SHP1 controls macrophage inflammation.

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Τίτλος: A druggable redox switch on SHP1 controls macrophage inflammation.
Συγγραφείς: Ng MY; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Nix MN; Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA.; Department of Chemistry, Stanford University, Stanford, CA, USA., Du G; Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA., Davidek I; Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA., Burger N; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Shin S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Toenjes S; Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA., Takeda H; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Cheah Xin Yan M; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Zhang B; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Xiao H; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Wei SM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Seo HS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Dhe-Paganon S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Wales TE; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA., Engen JR; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA., Mills EL; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Immunology, Harvard Medical School, Boston, MA, USA., Che J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. jianwei_che@dfci.harvard.edu., Zhang T; Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA. ztinghu8@stanford.edu., Gray NS; Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA. nsgray01@stanford.edu., Chouchani ET; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. edwardt_chouchani@dfci.harvard.edu.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. edwardt_chouchani@dfci.harvard.edu.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. edwardt_chouchani@dfci.harvard.edu.
Πηγή: Nature chemical biology [Nat Chem Biol] 2026 Jul; Vol. 22 (7), pp. 1187-1200. Date of Electronic Publication: 2026 Mar 12.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE
Imprint Name(s): Original Publication: New York, NY : Nature Pub. Group, [2005]-
Ιατρικοί όροι (MeSH): Protein Tyrosine Phosphatase, Non-Receptor Type 6*/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6*/chemistry , Macrophages*/drug effects , Macrophages*/metabolism , Macrophages*/immunology , Inflammation*/metabolism , Inflammation*/drug therapy, Cysteine/metabolism ; Cysteine/chemistry ; Cytokines/metabolism ; Signal Transduction/drug effects ; Oxidation-Reduction ; Animals ; Humans ; Mice
Περίληψη: Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting C102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.
(© 2026. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Competing Interests: Competing interests: E.T.C. is cofounder of Matchpoint Therapeutics and Aevum Therapeutics. J.C. is a cofounder of Matchpoint Therapeutics, scientific cofounder of M3 Bioinformatics and Technology and consultant and equity holder for Soltego and Allorion. N.S.G. is a founder, science advisory board member and equity holder for Syros, C4, Allorion, Lighthorse, Inception, Matchpoint, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The N.S.G. lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi. M.Y.N., M.N.N., G.D., E.T.C., J.C., T.Z. and N.S.G. are inventors on a patent WO/2025/109475 for the SHP1 compounds described in this work. The other authors declare no competing interests.
Σχόλια: Update of: bioRxiv. 2026 Feb 26:2026.02.19.706790. doi: 10.64898/2026.02.19.706790.. (PMID: 41757102)
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Grant Information: R01 DK123095 United States DK NIDDK NIH HHS; R56 AG071966 United States AG NIA NIH HHS; United States HHMI Howard Hughes Medical Institute; R01 AG071966 United States AG NIA NIH HHS; R01 AI175317 United States AI NIAID NIH HHS
Substance Nomenclature: EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
K848JZ4886 (Cysteine)
0 (Cytokines)
EC 3.1.3.48 (PTPN6 protein, human)
EC 3.1.3.48 (Ptpn6 protein, mouse)
Entry Date(s): Date Created: 20260313 Date Completed: 20260626 Latest Revision: 20260922
Update Code: 20260922
PubMed Central ID: PMC13070297
DOI: 10.1038/s41589-026-02163-8
PMID: 41820548
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1552-4469
DOI:10.1038/s41589-026-02163-8