Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes.
Autophagy is responsible for nonspecific, bulk degradation of cytoplasmic components. Recent work has revealed also that there is specific, autophagic degradation of polyubiquitinated protein aggregates, whose buildup occurs during neurodegenerative disease. Here, we report that simple mono-ubiquitination of normally long-lived cytoplasmic substrates is sufficient to target these substrates for autophagic degradation in mammalian cells. That is, upon their ubiquitination, both small [i.e., red fluorescent protein (RFP)] and large (i.e., peroxisomes) substrates are efficiently targeted to autophagosomes and then degraded within lysosomes upon autophagosome-lysosome fusion. This targeting requires the ubiquitin-binding protein, p62, and is blocked by the Class III phosphatidylinositol 3-kinase (PI3K) inhibitor, 3-methyladenine (3-MA), or by depletion of the autophagy-related-12 (Atg12) protein homolog. Mammalian cells thus use a common pathway involving ubiquitin and p62 for targeting diverse types of substrates for autophagy.
Kim
Peter Kijun
PK
Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Hailey
Dale Warren
DW
Mullen
Robert Thomas
RT
Lippincott-Schwartz
Jennifer
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071192:Autophagy-Related Protein 12; D019556:COS Cells; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000071456:Sequestosome-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000225:Adenine; D000071192:Autophagy-Related Protein 12; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000071456:Sequestosome-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins; D025801:Ubiquitin; C466624:ATG12 protein, human; C099718:SQSTM1 protein, human; C025946:3-methyladenine