Regulation of reticulophagy by the N-degron pathway

Chang Hoon Ji, Hee Yeon Kim, Ah Jung Heo, Min Ju Lee, Daniel Youngjae Park, Dong Hyun Kim, Bo Yeon Kim, Yong Tae Kwon

Research output: Contribution to journalComment/debate

Abstract

Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). In parallel, ER-residing molecular chaperones, such as HSPA5/GRP78/BiP, are relocated to the cytosol and conjugated with the amino acid L-arginine (Arg) at the N-termini by ATE1 (arginyltransferase 1). The resulting N-terminal Arg (Nt-Arg) binds the ZZ domain of SQSTM1, inducing oligomerization of SQSTM1-TRIM13 complexes and facilitating recruitment of LC3 on phagophores to the sites of reticulophagy. We developed small molecule ligands to the SQSTM1 ZZ domain and demonstrate that these chemical mimics of Nt-Arg facilitate reticulophagy and autophagic protein quality control of misfolded aggregates in the ER.

Original languageEnglish
Pages (from-to)373-375
Number of pages3
JournalAutophagy
Volume16
Issue number2
DOIs
StatePublished - 1 Feb 2020

Fingerprint

Endoplasmic Reticulum
arginyltransferase
Arginine
Ligands
Molecular Chaperones
Ubiquitin-Protein Ligases
Ubiquitination
Ubiquitin
Quality Control
Organelles
Cytosol
Lysine
Homeostasis
Amino Acids
Membranes
Proteins

Keywords

  • Alpha1-antitrypsin deficiency
  • ER homeostasis
  • ER protein quality control
  • ER stress response
  • ER-phagy
  • N-degron pathway
  • N-terminal arginylation
  • SQSTM1/p62
  • TRIM13
  • ubiquitination

Cite this

Ji, C. H., Kim, H. Y., Heo, A. J., Lee, M. J., Park, D. Y., Kim, D. H., ... Kwon, Y. T. (2020). Regulation of reticulophagy by the N-degron pathway. Autophagy, 16(2), 373-375. https://doi.org/10.1080/15548627.2019.1695402
Ji, Chang Hoon ; Kim, Hee Yeon ; Heo, Ah Jung ; Lee, Min Ju ; Park, Daniel Youngjae ; Kim, Dong Hyun ; Kim, Bo Yeon ; Kwon, Yong Tae. / Regulation of reticulophagy by the N-degron pathway. In: Autophagy. 2020 ; Vol. 16, No. 2. pp. 373-375.
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Ji, CH, Kim, HY, Heo, AJ, Lee, MJ, Park, DY, Kim, DH, Kim, BY & Kwon, YT 2020, 'Regulation of reticulophagy by the N-degron pathway', Autophagy, vol. 16, no. 2, pp. 373-375. https://doi.org/10.1080/15548627.2019.1695402

Regulation of reticulophagy by the N-degron pathway. / Ji, Chang Hoon; Kim, Hee Yeon; Heo, Ah Jung; Lee, Min Ju; Park, Daniel Youngjae; Kim, Dong Hyun; Kim, Bo Yeon; Kwon, Yong Tae.

In: Autophagy, Vol. 16, No. 2, 01.02.2020, p. 373-375.

Research output: Contribution to journalComment/debate

TY - JOUR

T1 - Regulation of reticulophagy by the N-degron pathway

AU - Ji, Chang Hoon

AU - Kim, Hee Yeon

AU - Heo, Ah Jung

AU - Lee, Min Ju

AU - Park, Daniel Youngjae

AU - Kim, Dong Hyun

AU - Kim, Bo Yeon

AU - Kwon, Yong Tae

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). In parallel, ER-residing molecular chaperones, such as HSPA5/GRP78/BiP, are relocated to the cytosol and conjugated with the amino acid L-arginine (Arg) at the N-termini by ATE1 (arginyltransferase 1). The resulting N-terminal Arg (Nt-Arg) binds the ZZ domain of SQSTM1, inducing oligomerization of SQSTM1-TRIM13 complexes and facilitating recruitment of LC3 on phagophores to the sites of reticulophagy. We developed small molecule ligands to the SQSTM1 ZZ domain and demonstrate that these chemical mimics of Nt-Arg facilitate reticulophagy and autophagic protein quality control of misfolded aggregates in the ER.

AB - Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). In parallel, ER-residing molecular chaperones, such as HSPA5/GRP78/BiP, are relocated to the cytosol and conjugated with the amino acid L-arginine (Arg) at the N-termini by ATE1 (arginyltransferase 1). The resulting N-terminal Arg (Nt-Arg) binds the ZZ domain of SQSTM1, inducing oligomerization of SQSTM1-TRIM13 complexes and facilitating recruitment of LC3 on phagophores to the sites of reticulophagy. We developed small molecule ligands to the SQSTM1 ZZ domain and demonstrate that these chemical mimics of Nt-Arg facilitate reticulophagy and autophagic protein quality control of misfolded aggregates in the ER.

KW - Alpha1-antitrypsin deficiency

KW - ER homeostasis

KW - ER protein quality control

KW - ER stress response

KW - ER-phagy

KW - N-degron pathway

KW - N-terminal arginylation

KW - SQSTM1/p62

KW - TRIM13

KW - ubiquitination

UR - http://www.scopus.com/inward/record.url?scp=85075740976&partnerID=8YFLogxK

U2 - 10.1080/15548627.2019.1695402

DO - 10.1080/15548627.2019.1695402

M3 - Comment/debate

C2 - 31744379

AN - SCOPUS:85075740976

VL - 16

SP - 373

EP - 375

JO - Autophagy

JF - Autophagy

SN - 1554-8627

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ER -

Ji CH, Kim HY, Heo AJ, Lee MJ, Park DY, Kim DH et al. Regulation of reticulophagy by the N-degron pathway. Autophagy. 2020 Feb 1;16(2):373-375. https://doi.org/10.1080/15548627.2019.1695402