RRC ID 64006
Author Najafov A, Luu HS, Mookhtiar AK, Mifflin L, Xia HG, Amin PP, Ordureau A, Wang H, Yuan J.
Title RIPK1 Promotes Energy Sensing by the mTORC1 Pathway.
Journal Mol Cell
Abstract 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.
Volume 81(2)
Pages 370-385.e7
Published 2021-1-21
DOI 10.1016/j.molcel.2020.11.008
PII S1097-2765(20)30786-3
PMID 33271062
MeSH AMP-Activated Protein Kinases / genetics AMP-Activated Protein Kinases / metabolism Animals Animals, Newborn Autophagy-Related Protein 5 / deficiency Autophagy-Related Protein 5 / genetics* Caspase 8 / genetics Caspase 8 / metabolism Cell Death / genetics Fas-Associated Death Domain Protein / deficiency Fas-Associated Death Domain Protein / genetics* Gene Expression Regulation Glucose / antagonists & inhibitors Glucose / pharmacology HEK293 Cells HT29 Cells Humans Intestine, Large / drug effects Intestine, Large / metabolism* Intestine, Large / pathology Jurkat Cells Lysosomes / drug effects Lysosomes / metabolism Lysosomes / pathology Mechanistic Target of Rapamycin Complex 1 / genetics* Mechanistic Target of Rapamycin Complex 1 / metabolism Metformin / antagonists & inhibitors Metformin / pharmacology Mice Mice, Inbred C57BL Mice, Knockout Phosphorylation Receptor-Interacting Protein Serine-Threonine Kinases / deficiency Receptor-Interacting Protein Serine-Threonine Kinases / genetics* Signal Transduction Sirolimus / pharmacology Tuberous Sclerosis Complex 2 Protein / genetics Tuberous Sclerosis Complex 2 Protein / metabolism
IF 15.584
Mice RBRC02231