Selective turnover of p62/A170/SQSTM1 by autophagy.
Loss of autophagy causes liver injury, cardiomyopathy and neurodegeneration, associated with the formation of ubiquitin-positive inclusion bodies. However, the pathogenic mechanism and molecular machinery involved in inclusion formation are not fully understood. We recently identified a ubiquitin-binding protein, p62/A170/SQSTM1, as a molecule involved in inclusion formation. p62 interacts with LC3 which regulates autophagosome formation, through an 11 amino acid sequence rich in acidic and hydrophobic residues, named the LC3-recognition sequence (LRS), and the LC3-p62 complex is degraded by autophagy. Furthermore, structural analysis reveals an interaction of Trp-340 and Leu-343 of p62 with different hydrophobic pockets in the ubiquitin-fold of LC3. p62 mutants, defective in binding the LRS, escape efficient turnover by autophagy, forming ubiquitin- and p62-positive inclusions. Importantly, such ubiquitin- and p62-positive inclusions are identified in various human diseases, implying the involvement of autophagy in their pathogenic mechanisms. Our reports identify an important role for autophagy in the selective turnover of p62, and demonstrate that in addition to the essential role of LC3 in autophagosome formation, LC3 is also involved in sorting autophagy-specific substrate(s).
Ichimura
Yoshinobu
Y
Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Kominami
Eiki
E
Tanaka
Keiji
K
Komatsu
Masaaki
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D000071456:Sequestosome-1 Protein
D048868:Adaptor Proteins, Signal Transducing; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase