LARP1 is a major phosphorylation substrate of mTORC1

Fonseca, B. D.; Jia, J.-J.; Hollensen, A. K.; Pointet, R.; Hoang, H.-D.; Niklaus, M. R.; Pena, I. A.; Lahr, R. M.; Smith, E. M.; Hearnden, J.; Wang, X.-D.; Yang, A.-D.; Celucci, G.; Graber, T. E.; Dajadian, C.; Yu, Y.; Damgaard, C. K.; Berman, A. J.; Alain, T.

doi:10.1101/491274

bioRxiv · 10.1101/491274

LARP1 is a major phosphorylation substrate of mTORC1

Fonseca, B. D.·Jia, J.-J.·Hollensen, A. K.·Pointet, R.·Hoang, H.-D.·Niklaus, M. R.·Pena, I. A.·Lahr, R. M.·Smith, E. M.·Hearnden, J.·Wang, X.-D.·Yang, A.-D.·Celucci, G.·Graber, T. E.·Dajadian, C.·Yu, Y.·Damgaard, C. K.·Berman, A. J.·Alain, T.

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Abstract

The mammalian target of rapamycin complex 1 (mTORC1) controls critical cellular functions such as protein synthesis, lipid metabolism, protein turnover and ribosome biogenesis through the phosphorylation of multiple substrates. In this study, we examined the phosphorylation of a recently identified target of mTORC1: La-related protein 1 (LARP1), a member of the LARP superfamily. Previously, we and others have shown that LARP1 plays an important role in repressing TOP mRNA translation downstream of mTORC1. LARP1 binds the 7-methylguanosine triphosphate (m7Gppp) cap moiety and the adjacent 5terminal oligopyrimidine (5TOP) motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 plays a critical role in the control of TOP mRNA translation via LARP1 but the precise mechanism by which this occurs is incompletely understood. The data described herein help to elucidate this process. Specifically, it show that: (i) mTORC1 interacts with LARP1, but not other LARP superfamily members, via the C-terminal region that comprises the DM15 domain, (ii) mTORC1 pathway controls the phosphorylation of multiple (up to 26) serine and threonine residues on LARP1 in vivo, (iii) mTORC1 regulates the binding of LARP1 to TOP mRNAs and (iv) phosphorylation of S689 by mTORC1 is particularly important for the association of the DM15 domain of LARP1 with the 5UTR of RPS6 TOP mRNA. These data reveal LARP1 as a major substrate of mTORC1.

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Fonseca, B. D., Jia, J.-J., Hollensen, A. K., Pointet, R., Hoang, H.-D., Niklaus, M. R., Pena, I. A., Lahr, R. M., Smith, E. M., Hearnden, J., Wang, X.-D., Yang, A.-D., Celucci, G., Graber, T. E., Dajadian, C., Yu, Y., Damgaard, C. K., Berman, A. J., Alain, T.. 2018-12-08. LARP1 is a major phosphorylation substrate of mTORC1. https://doi.org/10.1101/491274

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