Connexins modulate autophagosome biogenesis.
The plasma membrane contributes to the formation of autophagosomes, the double-membrane vesicles that sequester cytosolic cargo and deliver it to lysosomes for degradation during autophagy. In this study, we have identified a regulatory role for connexins (Cx), the main components of plasma membrane gap junctions, in autophagosome formation. We have found that plasma-membrane-localized Cx proteins constitutively downregulate autophagy through a direct interaction with several autophagy-related proteins involved in the initial steps of autophagosome formation, such as Atg16 and components of the PI(3)K autophagy initiation complex (Vps34, Beclin-1 and Vps15). On nutrient starvation, this inhibitory effect is released by the arrival of Atg14 to the Cx-Atg complex. This promotes the internalization of Cx-Atg along with Atg9, which is also recruited to the plasma membrane in response to starvation. Maturation of the Cx-containing pre-autophagosomes into autophagosomes leads to degradation of these endogenous inhibitors, allowing for sustained activation of autophagy.
Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Eloy
E
Bejarano
Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Andrea
A
Yuste
Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Bindi
B
Patel
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Randy F
RF
Stout
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
David C
DC
Spray
Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Ana Maria
AM
Cuervo
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D002462:Cell Membrane / Q000378:metabolism*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013217:Starvation / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D022161:Transport Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D058571:Vacuolar Sorting Protein VPS15 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D018031:Connexin 43; C500216:GJA1 protein, human; C543076:GJA1 protein, mouse; C580592:Gja1 protein, rat; D058546:Class III Phosphatidylinositol 3-Kinases; D058571:Vacuolar Sorting Protein VPS15