Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA

WeiChao Hao, MeiJuan Dian, Ying Zhou, QiuLing Zhong, WenQian Pang, ZiJian Li, YaYan Zhao, JiaCheng Ma, XiaoLin Lin, RenRu Luo, YongLong Li, JunShuang Jia, HongFen Shen, ShiHao Huang, GuanQi Dai, JiaHong Wang (), Yan Sun () and Dong Xiao ()
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WeiChao Hao: The First Affiliated Hospital of Guangdong Pharmaceutical University
MeiJuan Dian: Southern Medical University
Ying Zhou: Southern Medical University
QiuLing Zhong: Southern Medical University
WenQian Pang: Southern Medical University
ZiJian Li: Southern Medical University
YaYan Zhao: The First Affiliated Hospital of Guangdong Pharmaceutical University
JiaCheng Ma: Tsinghua University
XiaoLin Lin: Southern Medical University
RenRu Luo: Shenzhen Campus of Sun Yat-sen University
YongLong Li: Southern Medical University
JunShuang Jia: Southern Medical University
HongFen Shen: Southern Medical University
ShiHao Huang: Southern Medical University
GuanQi Dai: Southern Medical University
JiaHong Wang: Southern Medical University
Yan Sun: Guangdong Academy of Medical Sciences
Dong Xiao: Southern Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: Abstract Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m6A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m6A reader YTHDF3 is essential for autophagy induction. m6A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m6A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m6A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.

Date: 2022
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DOI: 10.1038/s41467-022-32963-0

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