Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1

• 成果类型: Article
• 署名作者: Malik, Nazma; Ferreira, Bibiana I.; Hollstein, Pablo E.; Curtis, Stephanie D.; Trefts, Elijah; Novak, Sammy Weiser; Yu, Jingting; Gilson, Rebecca; Hellberg, Kristina; Fang, Lingjing; Sheridan, Arlo; Hah, Nasun; Shadel, Gerald S.; Manor, Uri; Shaw, Reuben J.
• 署名单位: Salk Institute; Salk Institute; Salk Institute; Salk Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14110
• DOI: 10.1126/science.abj5559
• 发表日期: 2023-04-21
• 关键词: activated protein-kinase; skeletal-muscle; err-alpha; transcription factors; dependent regulation; energy-metabolism; tumor-suppressor; folliculin; pgc-1-alpha; network

摘要

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) and estrogen-related receptor alpha (ERRa) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.