Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP.
Autophagy, a lysosomal degradation pathway, is essential for homeostasis, development, neurological diseases, and cancer. Regulation of autophagy in human disease is not well understood. Atg9 is a transmembrane protein required for autophagy, and it has been proposed that trafficking of Atg9 may regulate autophagy. Mammalian Atg9 traffics between the TGN and endosomes in basal conditions, and newly formed autophagosomes in response to signals inducing autophagy. We identified p38IP as a new mAtg9 interactor and showed that this interaction is regulated by p38alpha MAPK. p38IP is required for starvation-induced mAtg9 trafficking and autophagosome formation. Manipulation of p38IP and p38alpha alters mAtg9 localization, suggesting p38alpha regulates, through p38IP, the starvation-induced mAtg9 trafficking to forming autophagosomes. Furthermore, we show that p38alpha is a negative regulator of both basal autophagy and starvation-induced autophagy, and suggest that this regulation may be through a direct competition with mAtg9 for binding to p38IP. Our results provide evidence for a link between the MAPK pathway and the control of autophagy through mAtg9 and p38IP.
Webber
Jemma L
JL
London Research Institute, Secretory Pathways Laboratory, Cancer Research UK, London, UK.
Tooze
Sharon A
SA
D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D008566:Membranes / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
C503283:ATG9B protein, human; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C502592:SUPT20H protein, human; D014157:Transcription Factors; D048308:Mitogen-Activated Protein Kinase 14