REPTOR and REPTOR-BP Regulate Organismal Metabolism and Transcription Downstream of TORC1.
TORC1 regulates growth and metabolism, in part, by influencing transcriptional programs. Here, we identify REPTOR and REPTOR-BP as transcription factors downstream of TORC1 that are required for ∼ 90% of the transcriptional induction that occurs upon TORC1 inhibition in Drosophila. Thus, REPTOR and REPTOR-BP are major effectors of the transcriptional stress response induced upon TORC1 inhibition, analogous to the role of FOXO downstream of Akt. We find that, when TORC1 is active, it phosphorylates REPTOR on Ser527 and Ser530, leading to REPTOR cytoplasmic retention. Upon TORC1 inhibition, REPTOR becomes dephosphorylated in a PP2A-dependent manner, shuttles into the nucleus, joins its partner REPTOR-BP to bind target genes, and activates their transcription. In vivo functional analysis using knockout flies reveals that REPTOR and REPTOR-BP play critical roles in maintaining energy homeostasis and promoting animal survival upon nutrient restriction.
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Marcel
M
Tiebe
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Marilena
M
Lutz
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Adriana
A
De La Garza
Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany.
Tina
T
Buechling
Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany.
Michael
M
Boutros
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: a.teleman@dkfz.de.
Aurelio A
AA
Teleman
D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D029721:Drosophila Proteins; D046912:Multiprotein Complexes; C000601322:REPTOR protein, Drosophila; C000601323:REPTOR-BP protein, Drosophila; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases