PXD055006-1

PXD055006 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.1 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 exploited 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 macrophages and in vivo, SCA and its analogues rapidly and selectively engage SHP1 Cys102 and antagonize IL-1 Receptor-Associated Kinase signaling, pro-inflammatory cytokine production, and lipopolysaccharide (LPS)-induced sepsis in mice. 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	2026-02-24
AnnouncementXML	Submission_2026-02-24_12:15:01.874.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Wales
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-19 13:27:11	ID requested
⏵ 1	2026-02-24 12:15:02	announced

Dataset with its publication pending

submitter keyword: SHP-1

HDX-MS

hydrogen/deuterium exchange mass spectrometry

covalent activator

Thomas E Wales
contact affiliation	Northeastern University
contact email	t.wales@northeastern.edu
lab head
Thomas Wales
contact affiliation	Northeastern University
contact email	t.wales@northeastern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055006
     1. Label: PRIDE project
     2. Name: A druggable redox switch on SHP1 controls macrophage inflammation