Loss of mTORC1 signalling impairs b-cell homeostasis and insulin processing

Blandino-Rosano M, Barbaresso R, Jimenez-Palomares M, Bozadjieva N, Werneck-de-Castro JP, Hatanaka M, Mirmira RG, Sonenberg N, Liu M, Rüegg MA, Hall MN, Bernal-Mizrachi E

Nature Communications 8, 16014 (2017)

Speaker: Hsi-Yu Liu (劉席羽)                                   Time: 13:10~14:00, Oct. 18, 2017

Commentator: Dr. Yun-Wen Chen (陳韻雯老師)          Place: Room 601

Abstract:

    The mTOR pathway links upstream nutrient availability and growth factor signalling to control metabolism, cell proliferation, and protein synthesis. The mTOR functions as two distinct multi-protein complexes termed mTOR complex 1 (mTORC1) and mTORC2. The mTORC1 contains six components, including mTOR, mLst/GbL, Deptor, Tti1/Tel2 complex, Raptor and PRAS40. Raptor and PRAS40 are specific to the mTORC1 complex, and deletion of Raptor inactivates this complex. The mTORC1 is activated by growth factors (insulin), nutrients (amino acids), and the cellular energy status (high ATP/AMP ratio). After activation, mTORC1 phosphorylates diverse substrates including S6K (ribosomal S6 kinase), 4E-BP (eIF4E-binding protein 1) and ULK1 (UNC-51-like kinase 1)¹. The S6K protein phosphorylates downstream substrates, such as ribosomal S6 protein and eIF4B, to promote mRNA translation and synthesis of ribosomes. Phosphorylation of 4E-BPs triggers their release from eIF4E and initiates cap-dependent translation of mRNAs with complex 50-untranslated region (UTR) structures. Deletion of raptor gene causes diabetes and b-cell failure due to defects in proliferation, autophagy, apoptosis, and insulin secretion. In this paper, authors investigated how mTORC1 inactivation induces b-cell failure using the mice with conditional raptor deletion in b-cells (braKO) and the mice with inducible deletion of raptor in mature b-cells (MIP-braKO^f/f). In addition, the authors performed genetic reconstitution of 4E-BP1-2/ eIF4E or S6K activity in braKO mice, and show that mTORC1 orchestrates a signalling response to regulate cell survival, b-cell mass and insulin secretion. Moreover, the authors reveal a novel role for the mTORC1/4E-BP2/eIF4E arm in the regulation of insulin processing by controlling cap-dependent translation of carboxypeptidase E (CPE).

Reference:

1          Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15, 155-162, doi:10.1038/nrm3757 (2014).