The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis
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The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis. / Sosna, Justyna; Voigt, Susann; Mathieu, Sabine; Kabelitz, Dieter; Trad, Ahmad; Janssen, Ottmar; Meyer-Schwesinger, Catherine; Schütze, Stefan; Adam, Dieter.
In: CELL COMMUN SIGNAL, Vol. 11, 01.01.2013, p. 76.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis
AU - Sosna, Justyna
AU - Voigt, Susann
AU - Mathieu, Sabine
AU - Kabelitz, Dieter
AU - Trad, Ahmad
AU - Janssen, Ottmar
AU - Meyer-Schwesinger, Catherine
AU - Schütze, Stefan
AU - Adam, Dieter
PY - 2013/1/1
Y1 - 2013/1/1
N2 - BACKGROUND: In 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.RESULTS: The 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.CONCLUSIONS: The 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.
AB - BACKGROUND: In 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.RESULTS: The 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.CONCLUSIONS: The 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.
KW - Animals
KW - Apoptosis
KW - Cells, Cultured
KW - HT29 Cells
KW - Humans
KW - Jurkat Cells
KW - Mice
KW - Mitochondrial Proteins
KW - NIH 3T3 Cells
KW - Podocytes
KW - Rats
KW - Rats, Wistar
KW - Serine Endopeptidases
KW - Tumor Necrosis Factor-alpha
KW - Ubiquitin Thiolesterase
U2 - 10.1186/1478-811X-11-76
DO - 10.1186/1478-811X-11-76
M3 - SCORING: Journal article
C2 - 24090154
VL - 11
SP - 76
JO - CELL COMMUN SIGNAL
JF - CELL COMMUN SIGNAL
SN - 1478-811X
ER -