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

Hi Jai R. Shin, Hyunkyung Kim, Sungryong Oh, Jun Gi Lee, Minjung Kee, Hyun Jeong Ko, Mi Na Kweon, Kyoung Jae Won, Sung Hee Baek

Research output: Contribution to journalArticlepeer-review

204 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)553-557
Number of pages5
JournalNature
Volume534
Issue number7608
DOIs
Publication statusPublished - 2016 Jun 15
Externally publishedYes

ASJC Scopus subject areas

  • General

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