Calmodulin regulates protease versus co-chaperone activity of a metacaspase
Anna Maria Eisele-Bürger,
Frederik Eisele,
Sandra Malmgren Hill,
Xinxin Hao,
Kara L. Schneider,
Rahmi Imamoglu,
David Balchin,
Beidong Liu,
F. Ulrich Hartl,
Peter V. Bozhkov,
Thomas Nyström
Affiliations
Anna Maria Eisele-Bürger
Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Molecular Sciences, Uppsala BioCenter, Swedish University of Agricultural Sciences and Linnean Center for Plant Biology, PO Box 7015, 75007 Uppsala, Sweden
Frederik Eisele
Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden
Sandra Malmgren Hill
Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden
Xinxin Hao
Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden
Kara L. Schneider
Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden
Rahmi Imamoglu
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
David Balchin
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
Beidong Liu
Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden
F. Ulrich Hartl
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
Peter V. Bozhkov
Department of Molecular Sciences, Uppsala BioCenter, Swedish University of Agricultural Sciences and Linnean Center for Plant Biology, PO Box 7015, 75007 Uppsala, Sweden; Corresponding author
Thomas Nyström
Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden; Corresponding author
Summary: Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.
