IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2009;1(2):127-142.

Review Article
Interplay between the ubiquitin-proteasome system and autophagy in

Qingwen Zheng, Jie Li, Xuejun Wang

Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 East Clark Street, Vermillion,
SD 57069, USA

Received April 28, 2009; accepted May 6, 2009; available online May 8, 2009

Abstract: Proteinopathies are a family of human disease caused by toxic aggregation-prone proteins and featured by the presence of
protein aggregates in the affected cells. The ubiquitin-proteasome system (UPS) and autopha-gy are two major intracellular protein
degradation pathways. The UPS mediates the targeted degradation of most normal proteins after performing their normal functions as
well as the removal of abnormal, soluble proteins. Autophagy is mainly responsible for degradation of defective organelles and the bulk
degradation of cytoplasm during starvation. The collaboration between the UPS and autophagy appears to be essential to protein
quality control in the cell. UPS proteolytic function often becomes inadequate in proteinopathies which may lead to acti-vation of
autophagy, striving to remove abnormal proteins especially the aggregated forms. HADC6, p62, and FoxO3 may play an important role
in mobilizing this proteolytic consortium. Benign measures to enhance protea-some function are currently lacking; however,
enhancement of autophagy via pharmacological intervention and/or lifestyle change has shown great promise in alleviating bona fide
proteinopathies in the cell and animal models. These pharmacological interventions are expected to be applied clinically to treat
human proteinopathies in the near future. (IJPPP904002).

Key words: Ubiquitin proteasome system; autophagy; proteinopathy; HADC6; p62; FoxO3

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Address all correspondence to:
Xuejun Wang, MD, PhD,
Division of Basic Biomedical Sciences
Sanford School of Medicine of the University of South Dakota
414 East Clark Street, Lee Medical Building
Vermillion, SD 57069
phone: 605 677-5132; fax: 605 677-6381