PXD072062

PXD072062 is an original dataset announced via ProteomeXchange.

Title	A druggable redox switch on SHP1 controls macrophage inflammation
Description	Immunological proteins are major disease targets, and the majority remain undrugged. Post-translational redox modification of protein cysteine residues has emerged as a mode of immune cell regulation, especially in the context of the macrophage cytokine response. 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 cysteines across diverse functional domains of immune-relevant proteins that are redox regulated in vivo. We demonstrate how these sites can be leveraged to develop cysteine-directed pharmacology, exemplified by a newfound cysteine activation site on the core immunological regulator SHP1. By targeting Cys102 on SHP1, we develop a highly selective covalent SHP1 agonist, SCA. SCA binding to Cys102 in the N-terminal Src Homology 2 (N-SH2) domain promotes its rearrangement to relieve auto-inhibition and drive SHP1 activation. In mouse and human macrophages, SCA and its analogues rapidly and selectively engage SHP1 Cys102 and antagonize interleukin-1 receptor-associated kinase signaling and lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production. Together, we discover a druggable cysteine redox switch controlling the macrophage cytokine response, and provide a compendium of functionally annotated redox regulated sites for cysteine-directed therapeutics development.
HostingRepository	PRIDE
AnnounceDate	2026-03-17
AnnouncementXML	Submission_2026-03-17_14:33:44.160.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mei Ying Ng
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-16 16:23:48	ID requested
⏵ 1	2026-03-17 14:33:44	announced

10.1038/S41589-026-02163-8;

submitter keyword: covalent agonist,chemoproteomics, SHP1

Edward T. Chouchani
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA.
contact email	edwardt_chouchani@dfci.harvard.edu
lab head
Mei Ying Ng
contact affiliation	Dana-Farber Cancer Institute, Harvard Medical School
contact email	meiy_ng@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD072062
     1. Label: PRIDE project
     2. Name: A druggable redox switch on SHP1 controls macrophage inflammation