eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy.
Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.
Ramírez-Valle
Francisco
F
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
Braunstein
Steve
S
Zavadil
Jiri
J
Formenti
Silvia C
SC
Schneider
Robert J
RJ
D001343:Autophagy / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D051336:Mitochondrial Membranes / Q000502:physiology; D011132:Polyribosomes / Q000648:ultrastructure; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases