Cullin-RING ligases in regulation of autophagy
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Cui et al. Cell Div (2016) 11:8 DOI 10.1186/s13008-016-0022-5
Open Access
REVIEW
Cullin‑RING ligases in regulation of autophagy Danrui Cui1,2, Xiufang Xiong2 and Yongchao Zhao1,2*
Abstract Cullin-RING ligases (CRLs), the largest E3 ubiquitin ligase family, promote ubiquitination and degradation of various cellular key regulators involved in a broad array of physiological and pathological processes, including cell cycle progression, signal transduction, transcription, cardiomyopathy, and tumorigenesis. Autophagy, an intracellular catabolic reaction that delivers cytoplasmic components to lysosomes for degradation, is crucial for cellular metabolism and homeostasis. The dysfunction of autophagy has been proved to associate with a variety of human diseases. Recent evidences revealed the emerging roles of CRLs in the regulation of autophagy. In this review, we will focus mainly on recent advances in our understandings of the regulation of autophagy by CRLs and the cross-talk between CRLs and autophagy, two degradation systems. We will also discuss the pathogenesis of human diseases associated with the dysregulation of CRLs and autophagy. Finally, we will discuss current efforts and future perspectives on basic and translational research on CRLs and autophagy. Keywords: CRL E3 ligase, UPS, Autophagy, mTOR, Ubiquitin, NEDD8, ATG Background The long-term health of a cell is closely associated with protein quality control which requires a well-regulated balance between protein synthesis and degradation [1]. It is critical for the maintenance of cellular homeostasis to eliminate unwanted and aberrant intracellular proteins, which is charged by both the ubiquitin–proteasome system (UPS) and the autophagy–lysosome system in a coordinated manner [2]. Thus, the dysregulation of UPS and autophagy disrupts cellular homeostasis and causes many human diseases, such as heart failure, neurodegeneration, and cancer [3, 4]. The UPS, a clearance system, directs target proteins with their lysine residues and the N-terminal methionine residue covalently attached by ubiquitin molecules, to the 26S proteasome for degradation, leading to the elimination of short-lived, misfolded, and damaged proteins [5–8]. Protein ubiquitination is a trio of enzymatic steps mediated by E1 (ubiquitin-activating enzyme), E2 *Correspondence: [email protected] 1 Key Laboratory of Combined Multi‑organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qing‑Chun Road, Hangzhou, Zhejiang 310003, People’s Republic of China Full list of author information is available at the end of the article
(ubiquitin-conjugating enzyme), and E3 (substrate-specific ubiquitin ligase) [9]. First, ubiquitin is activated in an ATP-dependent reaction catalyzed by E1. Second, the activated ubiquitin is transferred to the active site of an E2. Finally, an E3, which recognizes and recruits the target protein, designated as substrate, mediates the transfer of the activated ubiquitin directly to a lysine residue on
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