FKBP39 controls nutrient dependent Nprl3 expression and TORC1 activity in Drosophila.

Autor: Zhou Y; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Guo J; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Wang X; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Cheng Y; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Guan J; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Barman P; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Sun MA; Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China., Fu Y; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Wei W; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China., Feng C; College of Horticulture and Plant Protection, Yangzhou University, Yangzhou, 225009, China., Lilly MA; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. lillym@mail.nih.gov., Wei Y; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China. yhwei@yzu.edu.cn.; Animal Physiology Group, College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, China. yhwei@yzu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2021 Jun 02; Vol. 12 (6), pp. 571. Date of Electronic Publication: 2021 Jun 02.
DOI: 10.1038/s41419-021-03860-z
Abstrakt: Target of Rapamycin Complex 1 (TORC1) is a master regulator that coordinates nutrient status with cell metabolism. The GTPase-activating protein towards Rags complex 1 (GATOR1) inhibits TORC1 activity and protects cells from damage during periods of stress. Here we characterize multiple pathways that regulate the expression of the GATOR1 component Nprl3 in Drosophila. We determine that the stability of Nprl3 is impacted by the Unassembled Soluble Complex Proteins Degradation (USPD) pathway. In addition, we find that FK506 binding protein 39 (FKBP39)-dependent proteolytic destruction maintains Nprl3 at low levels in nutrient replete conditions. Nutrient starvation abrogates the degradation of the Nprl3 protein and rapidly promotes Nprl3 accumulation. Consistent with a role in promoting the stability of a TORC1 inhibitor, mutations in fkbp39 decrease TORC1 activity and increase autophagy. Finally, we show that the 5'UTR of nprl3 transcripts contain a functional upstream open reading frame (uORF) that inhibits main ORF translation. In summary, our work has uncovered novel mechanisms of Nprl3 regulation and identifies an important role for FKBP39 in the control of cellular metabolism.
Databáze: MEDLINE
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