A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions.
Autophagy is a cellular catabolic mechanism that plays an essential function in protecting multicellular eukaryotes from neurodegeneration, cancer, and other diseases. However, we still know very little about mechanisms regulating autophagy under normal homeostatic conditions when nutrients are not limiting. In a genome-wide human siRNA screen, we demonstrate that under normal nutrient conditions upregulation of autophagy requires the type III PI3 kinase, but not inhibition of mTORC1, the essential negative regulator of starvation-induced autophagy. We show that a group of growth factors and cytokines inhibit the type III PI3 kinase through multiple pathways, including the MAPK-ERK1/2, Stat3, Akt/Foxo3, and CXCR4/GPCR, which are all known to positively regulate cell growth and proliferation. Our study suggests that the type III PI3 kinase integrates diverse signals to regulate cellular levels of autophagy, and that autophagy and cell proliferation may represent two alternative cell fates that are regulated in a mutually exclusive manner.
Lipinski
Marta M
MM
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Hoffman
Greg
G
Ng
Aylwin
A
Zhou
Wen
W
Py
Bénédicte F
BF
Hsu
Emily
E
Liu
Xuxin
X
Eisenberg
Jason
J
Liu
Jun
J
Blenis
John
J
Xavier
Ramnik J
RJ
Yuan
Junying
J
D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005502:Food; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011506:Proteins; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics*
D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors