S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling.
S6 kinase 1 (S6K1) acts to integrate nutrient and growth factor signals to promote cell growth but also cell survival as a mitochondria-tethered protein kinase that phosphorylates and inactivates the proapoptotic molecule BAD. Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371. This activates a PP1gamma-dependent negative feedback program that decreases S6K1 activity and BAD phosphorylation, thereby altering the threshold for apoptosis. These findings establish URI and PP1gamma as integral components of an S6K1-regulated mitochondrial pathway dedicated, in part, to oppose sustained S6K1 survival signaling and to ensure that the mitochondrial threshold for apoptosis is set in accord with nutrient and growth factor availability.
Djouder
Nabil
N
Institute of Cell Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
Metzler
Stefan Christian
SC
Schmidt
Alexander
A
Wirbelauer
Christiane
C
Gstaiger
Matthias
M
Aebersold
Ruedi
R
Hess
Daniel
D
Krek
Wilhelm
W
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
C494819:BAD protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C117184:URI1 protein, human; D051025:bcl-Associated Death Protein; D012694:Serine; D019893:Ribosomal Protein S6 Kinases; D054645:Protein Phosphatase 1; D020123:Sirolimus