Mammalian Tribbles Homologs at the Crossroads of Endoplasmic Reticulum Stress and Mammalian Target of Rapamycin Pathways
Figure 2
TRB3 at the crossroads of ER stress and mTORC function. Acute and chronic kidney disease are associated with activation of the Endoplasmic Reticulum Stress pathway. During ER stress Protein kinase RNA (PKR)-like ER kinase (PERK) phosphorylates eukaryotic translation initiation factor α (eIF2α) and inhibits protein translation. Additionally, there is selective translation of activating transcription factor-4 (ATF4), which induces expression of C/EBP homologous protein (CHOP) and drives TRB3 expression. Kidney disease is also associated with activation of mTORC and inhibition of autophagy flux. We propose that in the kidney, TRB3 binds to Rictor and mTORC2 and inhibits phosphorylation of . This in turn reduces inflammatory gene expression (IL-6 and MCP-1) and potentially modifies activation of mTORC1 and autophagy.
