Journal
MOLECULAR CELL
Volume 75, Issue 5, Pages 1058-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.06.028
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Funding
- Seoul National University (SNU) Nobel Laureates Invitation Program
- National Research Foundation (NRF) - Ministry of Science, ICT, and Future Planning (MSIP) [NRF-2016R1A2B3011389, NRF-2017R1A2B2005629]
- RAMP
- D Convergence Program of the National Research Council of Science AMP
- Technology (NST) of Korea [CAP-16-03-KRIBB]
- Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program
- Dr. Miriam and Sheldon Adelson Medical Research Foundation (AMRF)
- Israel Cancer Research Fund (ICRF) Professorship
- Israel Science Foundation (ISF)
- National Research Foundation of Korea - Korea Ministry of Science, ICT, and Future Planning [SRC-2017R1A5A1014560]
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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.
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