ArticleCell communication and signaling : CCS2013
The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis.
Article in Cell communication and signaling : CCS, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 62 citations in OpenAlex.
- Targeting lysosome-dependent cell death in cancer: towards therapeutic strategies.Biomarker research · 2026Review
- Protocol for isolating human extracellular vesicles from nephrotic urine and enriching autoimmunoglobulin-triggered extracellular vesicles.STAR protocols · 2026Article
- Loss of ADAM15 prevents necroptosis induction by partial RIPK1 degradation due to enhanced TNF-R1 surface expression and basal caspase-8 activation.Cell communication and signaling : CCS · 2025Article
- Research progress on multiple cell death pathways of podocytes in diabetic kidney disease.Molecular medicine (Cambridge, Mass.) · 2023Review
- Protease-independent control of parthanatos by HtrA2/Omi.Cellular and molecular life sciences : CMLS · 2023Article
- Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.Nature communications · 2023Article
- High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease.Oxidative medicine and cellular longevity · 2023Article
- Modes of podocyte death in diabetic kidney disease: an update.Journal of nephrology · 2022Review
- Tripartite Separation of Glomerular Cell Types and Proteomes from Reporter-Free Mice.Journal of the American Society of Nephrology : JASN · 2021Article
- Controversies in Podocyte Loss: Death or Detachment?Frontiers in cell and developmental biology · 2021Review
- Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78).Scientific reports · 2020Article
- Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation.American journal of physiology. Heart and circulatory physiology · 2019Article
- Current translational potential and underlying molecular mechanisms of necroptosis.Cell death & disease · 2019Review
- Thrombospondin Type 1 Domain-Containing 7A Localizes to the Slit Diaphragm and Stabilizes Membrane Dynamics of Fully Differentiated Podocytes.Journal of the American Society of Nephrology : JASN · 2019Article
- Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells.Cell death & disease · 2019Article
- Article
- The role of necroptosis in the treatment of diseases.BMB reports · 2018Review
- Article
- Unique spectral signatures of the nucleic acid dye acridine orange can distinguish cell death by apoptosis and necroptosis.The Journal of cell biology · 2017Article
- Mitochondrial Quality Control Proteases in Neuronal Welfare.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2016Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundIn apoptosis, proteolysis by caspases is the primary mechanism for both initiation and execution of programmed cell death (PCD). In contrast, the impact of proteolysis on the regulation and execution of caspase-independent forms of PCD (programmed necrosis, necroptosis) is only marginally understood. Likewise, the identity of the involved proteases has remained largely obscure. Here, we have investigated the impact of proteases in TNF-induced necroptosis.
resultsThe serine protease inhibitor TPKC protected from TNF-induced necroptosis in multiple murine and human cells systems whereas inhibitors of metalloproteinases or calpain/cysteine and cathepsin proteases had no effect. A screen for proteins labeled by a fluorescent TPCK derivative in necroptotic cells identified HtrA2/Omi (a serine protease previously implicated in PCD) as a promising candidate. Demonstrating its functional impact, pharmacological inhibition or genetic deletion of HtrA2/Omi protected from TNF-induced necroptosis. Unlike in apoptosis, HtrA2/Omi did not cleave another protease, ubiquitin C-terminal hydrolase (UCH-L1) during TNF-induced necroptosis, but rather induced monoubiquitination indicative for UCH-L1 activation. Correspondingly, pharmacologic or RNA interference-mediated inhibition of UCH-L1 protected from TNF-induced necroptosis. We found that UCH-L1 is a mediator of caspase-independent, non-apoptotic cell death also in diseased kidney podocytes by measuring cleavage of the protein PARP-1, caspase activity, cell death and cell morphology. Indicating a role of TNF in this process, podocytes with stably downregulated UCH-L1 proved resistant to TNF-induced necroptosis.
conclusionsThe proteases HtrA2/Omi and UCH-L1 represent two key components of TNF-induced necroptosis, validating the relevance of proteolysis not only for apoptosis, but also for caspase-independent PCD. Since UCH-L1 clearly contributes to the non-apoptotic death of podocytes, interference with the necroptotic properties of HtrA2/Omi and UCH-L1 may prove beneficial for the treatment of patients, e.g. in kidney failure.
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