Abstract
The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size.
Highlights
The mammalian target of rapamycin has emerged as a critical nutritional and cellular energy checkpoint sensor and a regulator of cell growth [1,2,3] This evolutionary conserved Ser/Thr kinase is a member of the PIKK family of protein kinases [2] controlling many cellular processes, including protein synthesis, ribosome biogenesis, nutrient transport and autophagy [4]. mTOR assembles in two distinct multiprotein complexes, termed mTORC1 and mTORC2 [5,6]. mTORC1 consists of raptor, mLST8, PRAS40 and mTOR [7] and is sensitive to rapamycin. mTORC2 consists of rictor, mSIN1, mLST8 and mTOR [5,6]
We show in MAFbx-induced atrophy that the decreased activity of mTORC1 is correlated with the degradation of eIF3f and inversely mTOR and its downstream targets S6K1 and 4E-BP1 via eIF3f control muscle size. mTOR and S6K1 physically interact with two different domains of eIF3f
These data suggest that during muscle atrophy the decreased activity of mTORC1 is correlated with the degradation of eIF3f and the accumulation of unphosphorylated forms of S6K1
Summary
The mammalian target of rapamycin (mTOR, known as FRAP, RAFT1 or RAPT) has emerged as a critical nutritional and cellular energy checkpoint sensor and a regulator of cell growth [1,2,3] This evolutionary conserved Ser/Thr kinase is a member of the PIKK family of protein kinases [2] controlling many cellular processes, including protein synthesis, ribosome biogenesis, nutrient transport and autophagy [4]. mTOR assembles in two distinct multiprotein complexes, termed mTORC1 and mTORC2 [5,6]. mTORC1 consists of raptor (regulatory associated protein of mTOR), mLST8, PRAS40 and mTOR [7] and is sensitive to rapamycin. mTORC2 consists of rictor (rapamycin insensitive companion of mTOR), mSIN1, mLST8 and mTOR [5,6]. The mammalian target of rapamycin (mTOR, known as FRAP, RAFT1 or RAPT) has emerged as a critical nutritional and cellular energy checkpoint sensor and a regulator of cell growth [1,2,3] This evolutionary conserved Ser/Thr kinase is a member of the PIKK family of protein kinases [2] controlling many cellular processes, including protein synthesis, ribosome biogenesis, nutrient transport and autophagy [4]. MTORC1 consists of raptor (regulatory associated protein of mTOR), mLST8, PRAS40 and mTOR [7] and is sensitive to rapamycin. In response to growth factors, hormones and amino acids, mTORC1 is classically known to regulate cell growth and proliferation through modulation of protein synthesis by phosphorylation toward its downstream effectors, S6K1 [8] and 4E-BP1 [1]. The increased activation of S6 is linked to cellular growth control [12]
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