Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP
- Authors
- Cha-Molstad, Hyunjoo; Yu, Ji Eun; Lee, Su Hyun; Kim, Jung Gi; Sung, Ki Sa; Hwang, Joonsung; Yoo, Young Dong; Lee, Yoon Jee; Kim, Sung Tae; Lee, Dae Hee; Ciechanover, Aaron; Kim, Bo Yeon; Kwon, Yong Tae
- Issue Date
- 2016
- Publisher
- TAYLOR & FRANCIS INC
- Keywords
- ATE1 R-transferase; N-end rule pathway; protein arginylation; protein quality control; proteolysis
- Citation
- AUTOPHAGY, v.12, no.2, pp.426 - 428
- Indexed
- SCIE
SCOPUS
- Journal Title
- AUTOPHAGY
- Volume
- 12
- Number
- 2
- Start Page
- 426
- End Page
- 428
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/90132
- DOI
- 10.1080/15548627.2015.1126047
- ISSN
- 1554-8627
- Abstract
- The N-end rule pathway is a proteolytic system, in which single N-terminal residues act as a determinant of a class of degrons, called N-degrons. In the ubiquitin (Ub)-proteasome system, specific recognition components, called N-recognins, recognize N-degrons and accelerate polyubiquitination and proteasomal degradation of the substrates. In this study, we show that the pathway regulates the activity of the macroautophagic receptor SQSTM1/p62 (sequestosome 1) through N-terminal arginylation (Nt-arginylation) of endoplasmic reticulum (ER)-residing molecular chaperones, including HSPA5/GRP78/BiP, CALR (calreticulin), and PDI (protein disulfide isomerase). The arginylation is co-induced with macroautophagy (hereafter autophagy) as part of innate immunity to cytosolic DNA and when misfolded proteins accumulate under proteasomal inhibition. Following cytosolic relocalization and arginylation, Nt-arginylated HSPA5 (R-HSPA5) is targeted to autophagosomes and degraded by lysosomal hydrolases through the interaction of its N-terminal Arg (Nt-Arg) with ZZ domain of SQSTM1. Upon binding to Nt-Arg, SQSTM1 undergoes a conformational change, which promotes SQSTM1 self-polymerization and interaction with LC3, leading to SQSTM1 targeting to autophagosomes. Cargoes of R-HSPA5 include cytosolic misfolded proteins destined to be degraded through autophagy. Here, we discuss the mechanisms by which the N-end rule pathway regulates SQSTM1-dependent selective autophagy.
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