Doxorubicin induces caspase-mediated proteolysis of KV7.1

Anne Strigli; Christian Raab; Sabine Hessler; Tobias Huth; Adam J T Schuldt; Christian Alzheimer; Thomas Friedrich; Paul W Burridge; Mark Luedde; Michael Schwake

doi:10.1038/s42003-018-0162-z

Doxorubicin induces caspase-mediated proteolysis of KV7.1

Commun Biol. 2018 Sep 28:1:155. doi: 10.1038/s42003-018-0162-z. eCollection 2018.

Authors

Affiliations

¹ Institute of Biochemistry, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, 24118, Kiel, Germany.
² Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany.
³ Department of Pharmacology and Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Searle Building 8-450, Chicago, IL, 60611, USA.
⁴ Institut für Chemie PC 14, Technische Universität Berlin, Straße des 17. Juni 135, 10623, Berlin, Germany.
⁵ Department of Internal Medicine III, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany.
⁶ Institute of Biochemistry, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, 24118, Kiel, Germany. schwake@northwestern.edu.
⁷ Faculty of Chemistry/Biochemistry III, University of Bielefeld, Universitätsstr. 25, 33615, Bielefeld, Germany. schwake@northwestern.edu.
⁸ Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL, 60611-4296, USA. schwake@northwestern.edu.

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.