TY - JOUR
T1 - Integrated proteomics identifies p62-dependent selective autophagy of the supramolecular vault complex
AU - Kurusu, Reo
AU - Fujimoto, Yuki
AU - Morishita, Hideaki
AU - Noshiro, Daisuke
AU - Takada, Shuhei
AU - Yamano, Koji
AU - Tanaka, Hideaki
AU - Arai, Ritsuko
AU - Kageyama, Shun
AU - Funakoshi, Tomoko
AU - Komatsu-Hirota, Satoko
AU - Taka, Hikari
AU - Kazuno, Saiko
AU - Miura, Yoshiki
AU - Koike, Masato
AU - Wakai, Toshifumi
AU - Waguri, Satoshi
AU - Noda, Nobuo N.
AU - Komatsu, Masaaki
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/7/10
Y1 - 2023/7/10
N2 - In addition to membranous organelles, autophagy selectively degrades biomolecular condensates, in particular p62/SQSTM1 bodies, to prevent diseases including cancer. Evidence is growing regarding the mechanisms by which autophagy degrades p62 bodies, but little is known about their constituents. Here, we established a fluorescence-activated-particle-sorting-based purification method for p62 bodies using human cell lines and determined their constituents by mass spectrometry. Combined with mass spectrometry of selective-autophagy-defective mouse tissues, we identified vault, a large supramolecular complex, as a cargo within p62 bodies. Mechanistically, major vault protein directly interacts with NBR1, a p62-interacting protein, to recruit vault into p62 bodies for efficient degradation. This process, named vault-phagy, regulates homeostatic vault levels in vivo, and its impairment may be associated with non-alcoholic-steatohepatitis-derived hepatocellular carcinoma. Our study provides an approach to identifying phase-separation-mediated selective autophagy cargoes, expanding our understanding of the role of phase separation in proteostasis.
AB - In addition to membranous organelles, autophagy selectively degrades biomolecular condensates, in particular p62/SQSTM1 bodies, to prevent diseases including cancer. Evidence is growing regarding the mechanisms by which autophagy degrades p62 bodies, but little is known about their constituents. Here, we established a fluorescence-activated-particle-sorting-based purification method for p62 bodies using human cell lines and determined their constituents by mass spectrometry. Combined with mass spectrometry of selective-autophagy-defective mouse tissues, we identified vault, a large supramolecular complex, as a cargo within p62 bodies. Mechanistically, major vault protein directly interacts with NBR1, a p62-interacting protein, to recruit vault into p62 bodies for efficient degradation. This process, named vault-phagy, regulates homeostatic vault levels in vivo, and its impairment may be associated with non-alcoholic-steatohepatitis-derived hepatocellular carcinoma. Our study provides an approach to identifying phase-separation-mediated selective autophagy cargoes, expanding our understanding of the role of phase separation in proteostasis.
KW - Mallory-Denk body
KW - NBR1
KW - fluorescence-activated particle sorting
KW - hepatocellular carcinoma
KW - liquid-liquid phase separation
KW - non-alcoholic steatohepatitis
KW - p62/SQSTM1
KW - selective autophagy
KW - vault
KW - vault-phagy
UR - http://www.scopus.com/inward/record.url?scp=85163208786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85163208786&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2023.04.015
DO - 10.1016/j.devcel.2023.04.015
M3 - Article
C2 - 37192622
AN - SCOPUS:85163208786
SN - 1534-5807
VL - 58
SP - 1189-1205.e11
JO - Developmental Cell
JF - Developmental Cell
IS - 13
ER -