Molecular Cell
Volume 75, Issue 5, 5 September 2019, Pages 1058-1072.e9
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Article
The N-Degron Pathway Mediates ER-phagy

https://doi.org/10.1016/j.molcel.2019.06.028Get rights and content
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Highlights

  • The autophagic adaptor p62 mediates autophagic degradation of the ER (ER-phagy)

  • The ER membrane E3 ligase TRIM13 is a ubiquitin-dependent ER-phagy receptor to p62

  • N-terminal arginylation is an ER-phagy degron via binding to the ZZ domain of p62

  • p62-TRIM13-Nt-Arg circuit mediates ER protein quality control and homeostasis

Summary

The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.

Keywords

ER-phagy
endoplasmic reticulum
ER homeostasis
ER protein quality control
ER stress response
N-degron pathway
ubiquitination
N-terminal arginylation
p62
TRIM13
α1-antitrypsin deficiency

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These authors contributed equally

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