PKD2 deficiency suppresses amino acid biosynthesis in ADPKD by impairing the PERK-TBL2-eIF2ɑ-ATF4 pathway.

Abstract

Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism remain elusive. Here we report that amino acid biosynthesis is reprogrammed in Pkd2-knockout mouse kidneys via a defective PERK-eIF2ɑ-ATF4 pathway. Transcriptomic analysis revealed that the amino acid biosynthesis pathways such as serine, arginine and cysteine were impaired, and associated critical enzymes were downregulated in Pkd2-knockout mouse kidneys. ATF4 and CHOP, transcription factors downstream of the endoplasmic reticulum (ER) stress sensor PERK, were identified as master regulators of these enzymes' expression. PKD2 deficiency impaired the expression of ATF4 and amino acid synthesis enzymes in RCTEC cells under ER stress. Mechanistically, as an ER-resident protein, PKD2 interacts with TBL2, which functions as an adaptor bridging eIF2ɑ to PERK. PKD2 depletion impaired the recruitment of eIF2ɑ to TBL2, thus impeding activation of the PERK-eIF2ɑ-ATF4 pathway and downstream amino acid biosynthesis. These findings illuminate a molecular mechanism linking the PKD2-mediated PERK-eIF2ɑ-ATF4 pathway and amino acid metabolic reprogramming in ADPKD.

• Authors: Xingquan Zhou, Hui Xiong, Yi Lu, Meijuan Geng, Yumei Lu, Lirong Zhang, Xu Zhu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 561 Pg. 73-79 (07 05 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 34015761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• ATF4 protein, human
• Amino Acids
• Eukaryotic Initiation Factor-2
• TBL2 protein, human
• TRPP Cation Channels
• polycystic kidney disease 2 protein
• Activating Transcription Factor 4
• EIF2AK3 protein, human
• eIF-2 Kinase
• GTP-Binding Proteins

Topics

• Activating Transcription Factor 4 (metabolism)
• Amino Acids (biosynthesis)
• Animals
• Cells, Cultured
• Databases, Genetic
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism)
• Eukaryotic Initiation Factor-2 (metabolism)
• GTP-Binding Proteins (metabolism)
• Gene Expression Regulation
• Humans
• Mice
• Polycystic Kidney, Autosomal Dominant (metabolism, pathology)
• Signal Transduction
• TRPP Cation Channels (deficiency)
• eIF-2 Kinase (metabolism)