title: Amino-terminal arginylation as a degradation signal for selective autophagy.
abstract: The ubiquitin-proteasome system and the autophagy lysosome system are the two major protein degradation machineries in eukaryotic cells. These two systems coordinate the removal of unwanted intracellular materials, but the mechanism by which they achieve this synchronization is largely unknown. The ubiquitination of substrates serves as a universal degradation signal for both systems. Our study revealed that the amino-terminal Arg, a canonical N-degron in the ubiquitin-proteasome system, also acts as a degradation signal in autophagy. We showed that many ER residents, such as BiP, contain evolutionally conserved arginylation permissive pro-N-degrons, and that certain inducers like dsDNA or proteasome inhibitors cause their translocation into the cytoplasm where they bind misfolded proteins and undergo amino-terminal arginylation by arginyl transferase 1 (ATE1). The amino-terminal Arg of BiP binds p62, which triggers p62 oligomerization and enhances p62-LC3 interaction, thereby stimulating autophagic delivery and degradation of misfolded proteins, promoting cell survival. This study reveals a novel ubiquitin-independent mechanism for the selective autophagy pathway, and provides an insight into how these two major protein degradation pathways communicate in cells to dispose the unwanted proteins.
authors: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 28116, Korea.
authors: Hyunjoo
authors: H
authors: Cha-Molstad
authors: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea.
authors: Yong Tae
authors: YT
authors: Kwon
authors: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 28116, Korea.
authors: Bo Yeon
authors: BY
authors: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D019881:Aminoacyltransferases / Q000378:metabolism; D001120:Arginine / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D019295:Computational Biology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025801:Ubiquitin; D001120:Arginine; D019881:Aminoacyltransferases; C019727:arginyltransferase; D046988:Proteasome Endopeptidase Complex