Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
CHIP protects against cardiac pressure overload through regulation of AMPK
Jonathan C. Schisler, … , Douglas M. Cyr, Cam Patterson
Jonathan C. Schisler, … , Douglas M. Cyr, Cam Patterson
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3588-3599. https://doi.org/10.1172/JCI69080.
View: Text | PDF
Research Article Cardiology Article has an altmetric score of 13

CHIP protects against cardiac pressure overload through regulation of AMPK

  • Text
  • PDF
Abstract

Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in Chip–/– mice resulted in robust hypertrophy and decreased cardiac function and energy generation stemming from a failure to activate AMPK. Mechanistically, CHIP promoted LKB1-mediated phosphorylation of AMPK, increased the specific activity of AMPK, and was necessary and sufficient for stress-dependent activation of AMPK. CHIP-dependent effects on AMPK activity were accompanied by conformational changes specific to the α subunit, both in vitro and in vivo, identifying AMPK as the first physiological substrate for CHIP chaperone activity and establishing a link between cardiac proteolytic and metabolic pathways.

Authors

Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson

×

Figure 5

CHIP-dependent effects on AMPK tertiary structure.

Options: View larger image (or click on image) Download as PowerPoint
CHIP-dependent effects on AMPK tertiary structure.
(A) Limited proteolys...
(A) Limited proteolysis analysis of pAMPKα2β1γ1 in the presence of either luciferase (Luc) or CHIP. (B) Specific activity of AMPK in the presence of luciferase or CHIP prior to protease treatment (represented by mean ± SEM; Student’s t test, **P < 0.01; n = 3). (C) Nondigested pAMPKα2β1γ1 (A) or fragments of limited proteolysis reactions containing pAMPKα2β1γ1 in the presence of either luciferase (L) or CHIP (C) visualized with SYPRO-Ruby gel stain. (A and C) The white arrows indicate intact AMPKα2; the green arrows indicate intact γ1 subunit; and the red arrow indicates a fragment of AMPKα2 determined via protein sequencing that was detected only reactions containing CHIP. (D) Sequence of human AMPKα2 protein. The outlined area indicates the kinase domain, with the sequences identified by mass spectroscopy (red). (E) Representative live cell micrographs from before and after photobleaching conditions for both YFP and CFP channels and the resulting image ratio (CFPpost/pre) for cells cotransfected with a control vector (top) or CHIP expression vector (bottom). (F) Quantification of the apparent FRET efficiencies of AMPKα2 protein (cyan) or the positive control FRET protein (gray) coexpressed with the indicated vectors on the x axis (n = 45 cells from 3 independent transfections; ***P < 0.001 compared with pcDNA3 conditions; †P < 0.05 and ‡‡P < 0.01 compared with CHIP and CHIP(K30A), respectively, via ANOVA).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Referenced in 3 patents
52 readers on Mendeley
See more details