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Doxorubicin induces caspase-mediated proteolysis of KV7.1.

ABSTRACT: K_v7.1 (KCNQ1) coassembles with KCNE1 to generate the cardiac I_Ks -channel. Gain- and loss-of-function mutations in KCNQ1 are associated with cardiac arrhthymias, highlighting the importance of modulating I_Ks activity for cardiac function. Here, we report proteolysis of K_v7.1 as an irreversible posttranslational modification. The identification of two C-terminal fragments of K_v7.1 led us to identify an aspartate critical for the generation of one of the fragments and caspases as responsible for mediating proteolysis. Activating caspases reduces K_v7.1/KCNE1 currents, which is abrogated in cells expressing caspase-resistant channels. Enhanced cleavage of K_v7.1 can be detected for the LQT mutation G460S, which is located adjacent to the cleavage site, whereas a calmodulin-binding-deficient mutation impairs cleavage. Application of apoptotic stimuli or doxorubicin-induced cardiotoxicity provokes caspase-mediated cleavage of endogenous I_Ks in human cardiomyocytes. In summary, caspases are novel regulatory components of I_Ks channels that may have important implications for the molecular mechanism of doxorubicin-induced cardiotoxicity.

SUBMITTER: Strigli A

PROVIDER: S-EPMC6162258 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Doxorubicin induces caspase-mediated proteolysis of KV7.1.

Strigli Anne A Raab Christian C Hessler Sabine S Huth Tobias T Schuldt Adam J T AJT Alzheimer Christian C Friedrich Thomas T Burridge Paul W PW Luedde Mark M Schwake Michael M

Communications biology 20180928

Kv7.1 (KCNQ1) coassembles with KCNE1 to generate the cardiac IKs -channel. Gain- and loss-of-function mutations in KCNQ1 are associated with cardiac arrhthymias, highlighting the importance of modulating IKs activity for cardiac function. Here, we report proteolysis of Kv7.1 as an irreversible posttranslational modification. The identification of two C-terminal fragments of Kv7.1 led us to identify an aspartate critical for the ...[more]

PMID: 30302399

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Project description:Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. We report here that microglia activated through Toll-like receptors (TLRs) undergo RIP1/RIP3-dependent programmed necrosis (necroptosis) when exposed to the pan caspase inhibitor zVAD-fmk. Although zVAD-fmk and the caspase-8 inhibitor IETD-fmk had no effect on unstimulated primary microglia, they markedly sensitized microglia to TLR1/2,3,4,7/8 ligands or TNF treatment, triggering programmed necrosis that was completely blocked by R1P1 kinase inhibitor necrostatin-1. Interestingly, necroptosis induced by TLR ligands and zVAD was restricted to microglial cells and was not observed in astrocytes, neurons or oligodendrocytes even though they are known to express certain TLRs. Deletion of genes encoding TNF or TNFR1 failed to prevent lipopolysaccharide- and poly(I:C)-induced microglial necroptosis, unveiling a TNF-independent programmed necrosis pathway in TLR3- and TLR4-activated microglia. Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.

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Doxorubicin induces caspase-mediated proteolysis of KV7.1.

Publications

Doxorubicin induces caspase-mediated proteolysis of KV7.1.

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