AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy

TY - JOUR

T1 - AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy

AU - Shin, Hi-Jai R

AU - Kim, Hyunkyung

AU - Oh, Sungryong

AU - Lee, Jun-Gi

AU - Kee, Minjung

AU - Ko, Hyun-Jeong

AU - Kweon, Mi-Na

AU - Won, Kyoung-Jae

AU - Baek, Sung Hee

PY - 2016/6/15

Y1 - 2016/6/15

N2 - Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well studied, the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, we show that nutrient starvation results in AMP-activated protein kinase (AMPK)-dependent phosphorylation of FOXO3a in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 Arg17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional co-activator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB). Our findings demonstrate that CARM1-dependent histone arginine methylation is a crucial nuclear event in autophagy, and identify a new signalling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.

AB - Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well studied, the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, we show that nutrient starvation results in AMP-activated protein kinase (AMPK)-dependent phosphorylation of FOXO3a in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 Arg17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional co-activator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB). Our findings demonstrate that CARM1-dependent histone arginine methylation is a crucial nuclear event in autophagy, and identify a new signalling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.

KW - AMP-Activated Protein Kinases/metabolism

KW - Animals

KW - Arginine/metabolism

KW - Autophagy/genetics

KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism

KW - Cell Line

KW - Cell Nucleus/metabolism

KW - Food Deprivation

KW - Forkhead Box Protein O3

KW - Forkhead Transcription Factors/deficiency

KW - Histones/metabolism

KW - Humans

KW - Lysosomes/genetics

KW - Methylation

KW - Mice

KW - Phosphorylation

KW - Protein-Arginine N-Methyltransferases/metabolism

KW - S-Phase Kinase-Associated Proteins/antagonists & inhibitors

KW - SKP Cullin F-Box Protein Ligases/chemistry

KW - Signal Transduction

KW - Transcription, Genetic

U2 - 10.1038/nature18014

DO - 10.1038/nature18014

M3 - Journal article

C2 - 27309807

SN - 0028-0836

VL - 534

SP - 553

EP - 557

JO - Nature

JF - Nature

IS - 7608

ER -