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p97 is Critical for Cardiac Proteostasis and Dysregulation of p97 Activity Causes Cardiomyopathy
Author(s) -
Brody Matthew J,
Karch Jason,
Molkentin Jeffery D
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.816.6
Subject(s) - endoplasmic reticulum associated protein degradation , proteostasis , unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , aaa proteins , wild type , proteasome , protein degradation , ubiquitin , biology , downregulation and upregulation , protein folding , mutant , chemistry , atpase , biochemistry , enzyme , gene
Endoplasmic reticulum (ER)‐associated degradation (ERAD) is a protein quality control process whereby proteins that cannot be properly folded in the ER are retrotranslocated to the cytosol for degradation by the ubiquitin proteasome system. p97 is a AAA‐ATPase that forms a ring‐shaped hexameric structure on the cytosolic side of the ER membrane and provides the energy to retrotranslocate misfolded substrates from the ER for ultimate ubiquitin‐dependent degradation. Mutations in p97 are known to cause protein aggregation‐based diseases including pathologies of the nervous system, skeletal muscle, and heart. However, the role of p97 in cardiomyocytes has not been examined. Here, we generated cardiac‐specific transgenic mice overexpressing wildtype p97 or a p97 K524A mutant with deficient ATPase activity. Transgenic mice overexpressing wildtype p97 exhibit normal cardiac structure and function while mutant p97 overexpressing mice develop age‐dependent cardiomyopathy at baseline and greatly exacerbated cardiomyopathy in response to pressure overload. Mechanistically, both wiltype and mutant p97 overexpressing hearts upregulate the protein levels of Sel1l, an ERAD adaptor protein, while p97 K524A overexpressing hearts additionally upregulate the ERAD complex components OS‐9, Herp, and the ER‐resident prolyl isomerase cyclophilin B. Importantly, hearts overexpressing p97 K524A but not wildtype p97 have elevated levels of ubiquitinated proteins, indicating that p97 activity is required for efficient clearance of proteins targeted for proteasomal degradation. Moreover, overexpression of wildtype but not mutant p97 in cardiomyocytes enhanced ERAD activity and protected from ER stress induced cell death. These studies identify a critical role for p97 in cardiac proteostasis and demonstrate that dysregulation of p97 activity causes cardiomyopathy. Support or Funding Information This work was supported by a National Research Service Award (F32HL124698) from the National Institutes of Health to M.J.B. and grants from the Howard Hughes Medical Institute and National Institutes of Health (R01HL105924) to J.D.M.