Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding.

We show that ATE1-encoded Arg-transfer RNA transferase (R-transferase) of the N-end rule pathway mediates N-terminal arginylation of multiple endoplasmic reticulum (ER)-residing chaperones, leading to their cytosolic relocalization and turnover. N-terminal arginylation of BiP (also known as GRP78), protein disulphide isomerase and calreticulin is co-induced with autophagy during innate immune responses ...
to cytosolic foreign DNA or proteasomal inhibition, associated with increased ubiquitylation. Arginylated BiP (R-BiP) is induced by and associated with cytosolic misfolded proteins destined for p62 (also known as sequestosome 1, SQSTM1) bodies. R-BiP binds the autophagic adaptor p62 through the interaction of its N-terminal arginine with the p62 ZZ domain. This allosterically induces self-oligomerization and aggregation of p62 and increases p62 interaction with LC3, leading to p62 targeting to autophagosomes and selective lysosomal co-degradation of R-BiP and p62 together with associated cargoes. In this autophagic mechanism, Nt-arginine functions as a delivery determinant, a degron and an activating ligand. Bioinformatics analysis predicts that many ER residents use arginylation to regulate non-ER processes.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Aminoacyltransferases, Animals, Arginine, Autophagy, Cell Line, Tumor, Cells, Cultured, Embryo, Mammalian, Endoplasmic Reticulum, Fibroblasts, HEK293 Cells, HeLa Cells, Heat-Shock Proteins, Humans, Immunoblotting, Luminescent Proteins, Mice, Knockout, Microscopy, Confocal, Microtubule-Associated Proteins, Molecular Sequence Data, Protein Binding, RNA Interference, Sequence Homology, Amino Acid
Nat. Cell Biol.
Date: Jul. 01, 2015
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