[대학원 생명과학과 세미나 안내]
연사 : 권용태 교수(서울대학교 의과대학)
연제 : The N-end pathway in protein quality control:degradation of misfolded proteins by proteasome and autophagy
일시 : 2017년 3월 31일 (금) 오후 4시
장소 : 하나과학관 A동 109호
초청교수 : 송현규 교수
Abstract
The N-end rule pathway is a proteolytic system in which single N-terminal residues function as a class of degrons, called N-degrons. These degradation determinants are selectively recognized by specific recognition components, called N-recognins, leading to the targeting of substrates to cellular destructive machinery. One such degron, N-terminal arginine (Nt-Arg), is generated when ATE1-encoded Arg-tRNA transferase (R-transferase) conjugates the amino acid L-Arg to Nt-Asp or Nt-Glu. Our earlier work has identified a family of mammalian recognition components (UBR1, UBR2, UBR4/p600, and UBR5) characterized by the UBR box, a 70-residue zinc finger domain that can bind Nt-Arg for proteolysis. Upon binding N-degrons, these N-recognins can promote ubiquitination and proteasomal degradation. In this study, we found that ATE1 mediates Nt-arginylation of multiple Ca++-binding endoplasmic reticulum (ER)-residing chaperones, leading to their cytosolic accumulation. Nt-arginylation of BiP/GRP78, protein disulfide isomerase (PDI), and calreticulin (CRT) is coinduced with macroautophagy during various cellular stress responses, including innate immune responses to cytosolic double strand DNA (dsDNA) and autophagy-mediated quality control of misfolded proteins. Cargoes of arginylated BiP (R-BiP) include cytosolic misfolded proteins destined to autophagy. R-BiP binds the autophagic adaptor p62/sequestosome1/SQSTM1 through N-end rule interaction of its Nt-Arg to p62 ZZ domain. Upon binding to ZZ domain, Nt-Arg induces self-oligomerization and aggregation of p62 and p62 interaction with LC3, leading to the targeting p62 targeting to autophagosomes. This leads to selective lysosomal codegradation of R-BiP and p62 together with their cargoes. ATE1-deficient cells are hypersensitive to proteasomal inhibition associated with the impairments in autophagic induction, dsDNA-induced innate immune responses, and p62 targeting to autophagosomes. Bioinformatics analysis of the ER proteome predicts that many other ER residents may also utilize Nt-arginylation to regulate non-ER processes. These results suggest that the autophagy adaptor p62 is an N-recognin of the N-end rule pathway and mediates the cross-talk between the ubiquitin-proteasome system and autophagy through its ability to bind Nt-Arg and possibly other N-terminal residues.