RIPK1 Promotes Energy Sensing by the mTORC1 Pathway.

Autor:	Najafov A; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ayaz_najafov@hms.harvard.edu., Luu HS; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Mookhtiar AK; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Mifflin L; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Xia HG; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Amin PP; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Ordureau A; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Wang H; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Yuan J; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jyuan@hms.harvard.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Jan 21; Vol. 81 (2), pp. 370-385.e7. Date of Electronic Publication: 2020 Dec 02.
DOI:	10.1016/j.molcel.2020.11.008
Abstrakt:	The mechanisms of cellular energy sensing and AMPK-mediated mTORC1 inhibition are not fully delineated. Here, we discover that RIPK1 promotes mTORC1 inhibition during energetic stress. RIPK1 is involved in mediating the interaction between AMPK and TSC2 and facilitate TSC2 phosphorylation at Ser1387. RIPK1 loss results in a high basal mTORC1 activity that drives defective lysosomes in cells and mice, leading to accumulation of RIPK3 and CASP8 and sensitization to cell death. RIPK1-deficient cells are unable to cope with energetic stress and are vulnerable to low glucose levels and metformin. Inhibition of mTORC1 rescues the lysosomal defects and vulnerability to energetic stress and prolongs the survival of RIPK1-deficient neonatal mice. Thus, RIPK1 plays an important role in the cellular response to low energy levels and mediates AMPK-mTORC1 signaling. These findings shed light on the regulation of mTORC1 during energetic stress and unveil a point of crosstalk between pro-survival and pro-death pathways. Competing Interests: Declaration of Interests Junying Yuan is a consultant for Denali Therapeutics and Sanofi S.A. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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