RIPK1 Promotes Energy Sensing by the mTORC1 Pathway

Ayaz Najafov; Hoang Son Luu; Adnan K Mookhtiar; Lauren Mifflin; Hong-Guang Xia; Palak P Amin; Alban Ordureau; Huibing Wang; Junying Yuan

doi:10.1016/j.molcel.2020.11.008

RIPK1 Promotes Energy Sensing by the mTORC1 Pathway

Mol Cell. 2021 Jan 21;81(2):370-385.e7. doi: 10.1016/j.molcel.2020.11.008. Epub 2020 Dec 2.

Authors

Ayaz Najafov¹, Hoang Son Luu², Adnan K Mookhtiar², Lauren Mifflin², Hong-Guang Xia², Palak P Amin², Alban Ordureau², Huibing Wang², Junying Yuan³

Affiliations

¹ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
² Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

PMID: 33271062
DOI: 10.1016/j.molcel.2020.11.008

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.

Keywords: AMPK; CASP8; MLKL; RIPK1; RIPK3; TSC2; lysosome; mTORC1; neonatal lethality.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Atg5 protein, mouse
Autophagy-Related Protein 5
Fadd protein, mouse
Fas-Associated Death Domain Protein
Tsc2 protein, mouse
Tuberous Sclerosis Complex 2 Protein
Metformin
Mechanistic Target of Rapamycin Complex 1
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
Ripk3 protein, mouse
AMP-Activated Protein Kinases
Casp8 protein, mouse
Caspase 8
Glucose
Sirolimus