ArticleThe Journal of biological chemistry2014
Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 108 papers.
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Who cites it
108 citing papers in PubMed, 180 citations in OpenAlex.
- Gnao1 acts as a gatekeeper to alleviate neuropathic pain by silencing pro-nociceptive signaling cascades.The journal of headache and pain · 2026Article
- 25+ Years of TRPV4: From Discovery to Translational Horizons.Research square · 2026Article
- Monoclonal antibody inhibition of PAR2 reduces phenotype severity and pain in murine inflammatory bowel disease.Pain reports · 2026Article
- Cathepsins as Core Players in Obesity Pathogenesis: Emerging Therapeutic Targets.Biomolecules · 2026Review
- MMP1 and PRSS23 induce PARCommunications biology · 2026Article
- Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target.Molecular cancer research : MCR · 2026Review
- Modulation of Nociceptive Ion Channels by Protease-Activated Receptor-2 in Inflammatory Pain: Molecular Mechanisms and Therapeutic Potential.International journal of molecular sciences · 2026Review
- Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch.Frontiers in molecular neuroscience · 2026Article
- Macrophages Drive Ferroptosis Resistance after Radiotherapy.Cancer communications (London, England) · 2026Article
- Probing the activity of cysteine cathepsins in inflammatory bowel diseases.Scientific reports · 2025Article
- Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch.bioRxiv : the preprint server for biology · 2025Article
- Computational drug repurposing reveals Alectinib as a potential lead targeting Cathepsin S for therapeutic developments against cancer and chronic pain.Frontiers in bioinformatics · 2025Article
- Identification of Key Genes Mediated by N6-Methyladenosine Methyltransferase METTL3 in Ischemic Stroke via Bioinformatics Analysis and Experiments.Molecular biotechnology · 2025Article
- A QUARTER CENTURY OF CALCIUM-PERMEABLE ION CHANNEL, TRPV4: PERSPECTIVES ON EXPRESSION AND FUNCTION IN ENDOTHELIAL CELLS-TIME TO TRANSLATE.Transactions of the American Clinical and Climatological Association · 2025Review
- Cathepsin S: molecular mechanisms in inflammatory and immunological processes.Frontiers in immunology · 2025Review
- Inhibition of Cathepsin S in Autoimmune CD25KO Mouse Improves Sjögren Disease-Like Lacrimal Gland Pathology.Investigative ophthalmology & visual science · 2024Article
- Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects.International journal of molecular sciences · 2024Review
- Pathological mechanisms of cold and mechanical stress in modulating cancer progression.Human cell · 2024Review
- A machine learning algorithm for peripheral artery disease prognosis using biomarker data.iScience · 2024Article
- TRPV4 Activation and its Intracellular Modulation Mediated by Kinin Receptors Contribute to Painful Symptoms Induced by Anastrozole.Molecular neurobiology · 2024Article
48 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
19 authors at 6 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Serine proteases such as trypsin and mast cell tryptase cleave protease-activated receptor-2 (PAR2) at R(36)↓S(37) and reveal a tethered ligand that excites nociceptors, causing neurogenic inflammation and pain. Whether proteases that cleave PAR2 at distinct sites are biased agonists that also induce inflammation and pain is unexplored. Cathepsin S (Cat-S) is a lysosomal cysteine protease of antigen-presenting cells that is secreted during inflammation and which retains activity at extracellular pH. We observed that Cat-S cleaved PAR2 at E(56)↓T(57), which removed the canonical tethered ligand and prevented trypsin activation. In HEK and KNRK cell lines and in nociceptive neurons of mouse dorsal root ganglia, Cat-S and a decapeptide mimicking the Cat-S-revealed tethered ligand-stimulated PAR2 coupling to Gαs and formation of cAMP. In contrast to trypsin, Cat-S did not mobilize intracellular Ca(2+), activate ERK1/2, recruit β-arrestins, or induce PAR2 endocytosis. Cat-S caused PAR2-dependent activation of transient receptor potential vanilloid 4 (TRPV4) in Xenopus laevis oocytes, HEK cells and nociceptive neurons, and stimulated neuronal hyperexcitability by adenylyl cyclase and protein kinase A-dependent mechanisms. Intraplantar injection of Cat-S caused inflammation and hyperalgesia in mice that was attenuated by PAR2 or TRPV4 deletion and adenylyl cyclase inhibition. Cat-S and PAR2 antagonists suppressed formalin-induced inflammation and pain, which implicates endogenous Cat-S and PAR2 in inflammatory pain. Our results identify Cat-S as a biased agonist of PAR2 that causes PAR2- and TRPV4-dependent inflammation and pain. They expand the role of PAR2 as a mediator of protease-driven inflammatory pain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.