2. Academic Validation
  3. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA

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

  • Nat Commun. 2022 Oct 4;13(1):5845. doi: 10.1038/s41467-022-32963-0.
WeiChao Hao  # 1 2,  MeiJuan Dian  # 3 4,  Ying Zhou 2 4,  QiuLing Zhong 5,  WenQian Pang 2,  ZiJian Li 2,  YaYan Zhao 1,  JiaCheng Ma 6,  XiaoLin Lin 2 7,  RenRu Luo 8,  YongLong Li 2 4,  JunShuang Jia 2,  HongFen Shen 2,  ShiHao Huang 2 4,  GuanQi Dai 2 4,  JiaHong Wang 9,  Yan Sun 10,  Dong Xiao 11 12 13
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, 510080, Guangzhou, China.
  • 2 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China.
  • 3 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
  • 4 Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, 510515, Guangzhou, China.
  • 5 Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China.
  • 6 Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, 10084, Beijing, China.
  • 7 Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China.
  • 8 School of Medicine, Shenzhen Campus of Sun Yat-sen University, 518107, Guangdong, China.
  • 9 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China. wjh1987@smu.edu.cn.
  • 10 Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080, Guangzhou, China. sunyan@gdph.org.cn.
  • 11 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China. xiaodong@smu.edu.cn.
  • 12 Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, 510515, Guangzhou, China. xiaodong@smu.edu.cn.
  • 13 National Demonstration Center for Experimental Education of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China. xiaodong@smu.edu.cn.
  • # Contributed equally.
PMID: 36195598 DOI: 10.1038/s41467-022-32963-0
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.

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