Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs.
Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes through Foxk-Sin3-mediated transcriptional control.
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Christopher John
CJ
Bowman
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
Donald E
DE
Ayer
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Brian David
BD
Dynlacht
D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000473:pathology; D009752:Nutritional Status / Q000502:physiology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015533:Transcriptional Activation
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C497672:Foxk1 protein, mouse; D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C115812:Sin3b protein, mouse; C070635:interleukin binding factor; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex