Cathepsin S Signals via PAR2 and Generates a Novel Tethered Ligand Receptor Agonist

Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation

Cathepsin S Signals via PAR2 and Generates a Novel Tethered Ligand Receptor Agonist

Abstract Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation

Factors associated with survival in a contemporary adult sickle cell disease cohort: Factors Associated with Survival in Sickle Cell Disease

We examined the relationship of clinical differences among sickle cell disease (SCD) patients in order to understand the major contributors to early mortality in a contemporary cohort

Metabolomics of Chronic Kidney Disease Progression: A Case-Control Analysis in the Chronic Renal Insufficiency Cohort Study

Whereas several longitudinal metabolomics studies have been conducted in individuals with normal eGFR at baseline, disease progression among individuals with established CKD has not been rigorously examined

Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation in Diabetic and Non-Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Diabetic patients account for an increasing number of patients undergoing percutaneous coronary intervention (PCI). However, diabetes mellitus (DM) is associated with increased residual platelet activity during dual antiplatelet treatment (DAPT) and DM patients have worse clinical outcomes after PCI as compared to non DM

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies

Final version published online 17 February 2023There is increasing recognition that pathogenic germline variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germline predisposition variants have different post-transplant outcomes compared to those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germline variants (DGVs) and 34% underwent HSCT. DGVs in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germline DDX41 variants had a higher incidence of severe (stage 3-4) acute graft versus host disease (GVHD) (38%) compared to recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germline variants (9%) (p= 0.002). Importantly, the use of post-transplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germline DDX41-associated myeloid neoplasms (0% vs 53%, p=0.03). Based on these results, we advocate the use of post-transplant cyclophosphamide when individuals with deleterious germline DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.Caner Saygin, Gregory Roloff, Christopher N. Hahn, Rakchha Chhetri, Saar Gill, Hany Elmariah, Chetasi Talati, Emma Nunley, Guimin Gao, Aelin Kim, Michael Bishop, Satyajit Kosuri, Soma Das, Deepak Singhal, Parvathy Venugopal, Claire C. Homan, Anna Brown, Hamish S. Scott, Devendra Hiwase, and Lucy A. Godle

Synapses on demand require dendrites at the ready: How defining stages of dendritic development in vitro could inform studies of behaviorally driven information storage in the brain

Bill Greenough's work provides a framework for thinking about synaptogenesis not only as a key step in the initial wiring of neural systems according to a species typical plan (i.e., experience‐expectant development), but also as a mechanism for storing information based an individual's unique experience over its lifetime (i.e., experience‐dependent plasticity). Analysis of synaptic development in vitro brings a new opportunity to test the limits of expectant‐expectant development at the level of the individual neuron. We analyzed dendritic growth, synapse formation, and the development of specialized cytoplasmic microdomains during development in cultured hippocampal neurons, to determine if the timing of each of these events is correlated. Taken together, the findings reported here support the hypotheses that (1) dendritic development is rate limiting in synapse formation and (2) synaptic circuits are assembled in a step‐wise fashion consistent with a stage‐specific shift from genomically pre‐programmed to activity‐dependent mechanisms. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:443–455, 2011.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86892/1/20560_ftp.pd