Polymorphisms in the cathepsin L2 (CTSL2) gene show association with type 1 diabetes and early-onset myasthenia gravis

Viken, Marte K.; Sollid, Hege Dahlen; Joner, Geir; Dahl‐Jørgensen, Knut; Rønningen, Kjersti S.; Undlien, Dag E.; Flatø, Berit; Selvaag, Anne M; Førre, Ø; Kvien, Tore K; Thorsby, E.; Melms, Arthur; Tolosa, Eva; Lie, Benedicte A.

doi:10.1016/j.humimm.2007.05.009

Cited by 32 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibitors selective for cathepsin L and V are just emerging (113) and will prove useful in determining their individuals functions. Furthermore, the search for disease associations with expression or genetic polymorphisms of cathepsins (114)(115)(116), together with functional analysis of human cells and mouse experiments combining gene knockouts with transgenic expression of the human proteases, have already provided valuable insights into the specific in vivo functions of human cathepsins L and V (74,117,118). In summary, the complex phylogeny, the widespread expression of cathepsin L-like enzymes, and the multiple phenotypes of the gene knockout mice highlight the great importance of the cathepsin L-like proteases in physiology and disease processes.…”

Section: Cysteine Cathepsins In Humans and Micementioning

confidence: 99%

Specialized roles for cysteine cathepsins in health and disease

Reiser

Adair²,

Reinheckel³

2010

J. Clin. Invest.

502

403

View full text Add to dashboard Cite

A primer on cathepsin biology Cathepsin L transcription and translation. Substantial work has beendone to analyze the promoter regions of the human cathepsin L gene (CTSL) promoter as well as to understand the regulation of different splice variants within the 5′ untranslated region of the transcript (21,22). Of note, one of the splice variants contains a functional internal ribosomal entry site that enables ongoing translation of human cathepsin L under stress conditions, and hypoxia can shut down cap-dependent translation initiation (23). More recent work has focused on the regulation of cathepsin L alternative translation. According to the presence of different forms of cathepsin L in distinct subcellular and extracellular compartments, cathepsin L proteins can be initiated from downstream AUG sites (10), omitting the signal peptide that is normally present at the N terminus of lysosomal cathepsin L that routes the protein to the ER during its synthesis (Figure 2) (10, 24-26 Cathepsins were originally identified as proteases that act in the lysosome. Recent work has uncovered nontraditional roles for cathepsins in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized cathepsins participate in many physiologic and pathophysiologic cellular processes, in which they can act as both digestive and regulatory proteases. In this review, we discuss the transcriptional and translational control of cathepsin expression, the regulation of intracellular sorting of cathepsins, and the structural basis of cathepsin activation and inhibition. In particular, we highlight the emerging roles of various cathepsin forms in disease, particularly those of the cardiac and renal systems.

show abstract

Section: Cysteine Cathepsins In Humans and Micementioning

confidence: 99%

Specialized roles for cysteine cathepsins in health and disease

Reiser

Adair²,

Reinheckel³

2010

J. Clin. Invest.

502

403

View full text Add to dashboard Cite

show abstract

“…We found that the proteases cathepsin V and cathepsin L can cleave RTYSLTT at both cleavage sites. Cathepsin V has been reported to be associated with type 1 diabetes [27], and cathepsin L activity can control adipogenesis and glucose tolerance [28].…”

Section: Discussionmentioning

confidence: 99%

Early Second-Trimester Peptidomic Identification of Serum Peptides for Potential Prediction of Gestational Diabetes Mellitus

Yin

Huai

Zhao

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Early screening and diagnosis is important for minimizing gestational adverse outcomes. Routine screening of gestational diabetes mellitus (GDM) at 24–28 weeks with 75 g oral glucose challenge test (OGCT) leaves limited time for intervention and prevention. This study aims to analyze maternal serum peptides in the early second-trimester for prediction of gestational diabetes mellitus (GDM). Methods: Serum samples were collected from 16-18-week pregnant women that visited Nanjing Maternity and Child Health Care Hospital from April to August 2015. According to gestational outcome with or without GDM in late pregnancy, 200 of serum samples from GDM mothers and controls were randomly divided into two subgroups. Peptidomic identification of serum peptides was performed by combining ultrafiltration and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the differentially-expressed peptides between two groups. Results: A total of 297 identified peptides, originating from 228 proteins, were significantly differentially expressed in the GDM group compared with control. These precursor proteins may play critical roles in cell death of cortical neurons, elongation of cellular protrusions, and stabilization of microtubules. Major networks identified included those involving lipid metabolism, molecular transport and small molecule biochemistry. Conclusion: We provide for the first time a validated peptidome profile of early second-trimester serum in normal and GDM mothers, and we investigated the potential serum biomarkers for GDM. We concluded that 297 peptides could serve as potential biomarkers for GDM.

show abstract

“…While initial biodistribution studies only demonstrated expression of cathepsin V in testis, thymus and within the corneal epithelium (53), it has since been detected in skin (54), endothelial cells (55), breast and colorectal carcinomas (56) and human PBMCs (55). Polymorphisms of cathepsin V have been associated with diabetes and early onset myasthenia gravis (57). Absence of cathepsin V in mice (carrying the cathepsin L homologue) limits our in vivo murine models in establishing a direct link to cathepsin V. We do show, however, that SQV protects the TLR4-HMGB1-induced pathology.…”

Section: Discussionmentioning

confidence: 99%

The HIV Protease Inhibitor Saquinavir Inhibits HMGBl-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88

Pribis

Al‐Abed

Yang

et al. 2015

Mol Med

View full text Add to dashboard Cite

Extracellular high-mobility group box 1 (HMGB1) (disulfide form), via activation of toll-like receptor 4 (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1-induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macrophages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334 or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4-driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a firstgeneration PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation. teraction of the complex with the cognate receptor of the ligand-binding partner (3). Second, the redox status of the three cysteines (C23, C45 and C106) within HMGB1 determines both the efficiency of binding to other ligands as well as the specificity of HMGB1 for certain receptors (5). For example, when in the all-thiol configuration, HMGB1 binds to CXCL12 (SDF1) to amplify the activation of CXCR4 on immune and progenitor cells promoting chemotaxis. In contrast, under mild oxidizing conditions, C23 and C45 can form a disulfide bond an...

show abstract

Polymorphisms in the cathepsin L2 (CTSL2) gene show association with type 1 diabetes and early-onset myasthenia gravis

Cited by 32 publications

References 32 publications

Specialized roles for cysteine cathepsins in health and disease

Specialized roles for cysteine cathepsins in health and disease

Early Second-Trimester Peptidomic Identification of Serum Peptides for Potential Prediction of Gestational Diabetes Mellitus

The HIV Protease Inhibitor Saquinavir Inhibits HMGBl-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88

Contact Info

Product

Resources

About