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<p>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.</p><p></p>

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A druggable redox switch on SHP1 controls macrophage inflammation

  • 期刊论文

  • 发表日期：

    2026年3月12日

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  • Mei Ying Ng,
  • Meredith N. Nix,
  • Guangyan Du,
  • Ivan Davidek,
  • Nils Burger,
  • Sanghee Shin,
  • Sean Toenjes,
  • Haruna Takeda,
  • Megan Cheah Xin Yan,
  • Bingsen Zhang,
  • Haopeng Xiao,
  • Shelley M. Wei,
  • Hyuk-Soo Seo,
  • Sirano Dhe-Paganon,
  • Thomas E. Wales,
  • John R. Engen,
  • Evanna L. Mills,
  • Jianwei Che,
  • Tinghu Zhang,
  • Nathanael S. Gray,
  • Edward T. Chouchani

摘要

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.