Am J Cardiovasc Dis 2011;1(3):214-226

Original Article
Proteasome malfunction activates macroautophagy in the heart

Qingwen Zheng, Huabo Su, Zongwen Tian, Xuejun Wang

Protein Quality Control and Degradation Research Center, Division of Basic Biomedical Sciences, Sanford School of
Medicine of the University of South Dakota, Vermillion, SD 57069, USA.

Received July 4, 2011; accepted July 16, 2011; Epub July 28, 2011; published September 30, 2011

Abstract: Protein quality control (PQC) senses and repairs misfolded/unfolded proteins and, if the repair fails, degrade the
terminally misfolded polypeptides through an intricate collaboration between molecular chaperones and targeted
proteolysis. Proteolysis of damaged proteins is performed primarily by the ubiquitin-proteasome system (UPS).
Macroautophagy (commonly known as autophagy) may also play a role in PQCassociated proteolysis, especially when
UPS function becomes inadequate. The development of a range of heart diseases, including bona fide cardiac
proteinopathies and various forms of cardiac dysfunction has been linked to proteasome functional insufficiency (PFI). Both
PFI and activation of autophagy have been observed in the heart of well-established mouse models of cardiac
proteinopathy. A causal relationship between PFI and autophagic activation was suggested by a study using cultured
cardiomyocytes but has not been established in the heart of intact animals. Taking advantage of an autophagy reporter, we
demonstrated here that pharmacologically induced proteasome inhibition is sufficient to activate autophagy in
cardiomyocytes in both intact animals and cell cultures, unveiling a potential cross-talk between the two major degradation
pathways in cardiac PQC. (AJCD1107004).

Keywords: Proteasome, autophagy, autophagic flux, cardiomyocytes, mice

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Address all correspondence to:
Xuejun Wang, MD, PhD
Protein Quality Control and Degradation Research Center
Division of Basic Biomedical Sciences
Sanford School of Medicine of the University of South Dakota
414 East Clark Street, Lee Medical building, SD 57069, USA.
Tel. 605 677-5132; Fax. 605 677-6381
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