Early endosomes and endosomal coatomer are required for autophagy.
Autophagy, an intracellular degradative pathway, maintains cell homeostasis under normal and stress conditions. Nascent double-membrane autophagosomes sequester and enclose cytosolic components and organelles, and subsequently fuse with the endosomal pathway allowing content degradation. Autophagy requires fusion of autophagosomes with late endosomes, but it is not known if fusion with early endosomes is essential. We show that fusion of AVs with functional early endosomes is required for autophagy. Inhibition of early endosome function by loss of COPI subunits (beta', beta, or alpha) results in accumulation of autophagosomes, but not an increased autophagic flux. COPI is required for ER-Golgi transport and early endosome maturation. Although loss of COPI results in the fragmentation of the Golgi, this does not induce the formation of autophagosomes. Loss of COPI causes defects in early endosome function, as both transferrin recycling and EGF internalization and degradation are impaired, and this loss of function causes an inhibition of autophagy, an accumulation of p62/SQSTM-1, and ubiquitinated proteins in autophagosomes.
London Research Institute, Cancer Research UK, London WC2A 3PX, England, UK.
Minoo
M
Razi
Edmond Y W
EY
Chan
Sharon A
SA
Tooze
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D020755:Coat Protein Complex I / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D014168:Transferrin / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D020755:Coat Protein Complex I; C084004:LMAN1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; D052119:Lysosomal-Associated Membrane Protein 2; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C072237:TGOLN2 protein, human; D014168:Transferrin; D025801:Ubiquitin