Physiological/pathological ramifications of transcription factors in the unfolded protein response

Abstract

Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery as a Strategy for Co-opting Host Cell Protein Synthesis

“…While most transcriptome-wide changes in total translation were driven by changes in mRNA levels, changes in DENV-only genes and IFN-induced genes were primarily driven by changes in translational efficiency. The activation of the UPR was primarily transcriptional, likely through the activation of the UPR-linked transcription factors XBP-1, ATF4, and CHOP (71)(72)(73).…”

Biosynthesis, structure, and folding of the insulin precursor protein

“…The most ancient, conserved ER stress response (unfolded protein response, or UPR) is signalled through activation of the inositol‐requiring enzyme 1 (IRE1), a protein kinase and endoribonuclease (described below). Two more recent evolutionary developments in ER stress signalling include the protein kinase‐like endoplasmic reticulum kinase (PERK) and the transcription factor ATF6 It is generally believed that both active and inactive subpopulations of the three ER stress sensors co‐exist in normal cells, with the proportion of the active subfractions linked to cellular physiology and secretory pathway activity.…”

“…Two more recent evolutionary developments in ER stress signalling include the protein kinase-like endoplasmic reticulum kinase (PERK) and the transcription factor ATF6. [134][135][136] " It is generally believed that both active and inactive subpopulations of the three ER stress sensors co-exist in normal cells, with the proportion of the active subfractions linked to cellular physiology and secretory pathway activity. "…”

Claspin – checkpoint adaptor and DNA replication factor

“…; ). The UPR activates a complex program of gene expression through multiple transcriptional effectors such as ATF4, ATF6 and XBP1, to maintain cellular homeostasis under conditions of ER stress . It is therefore possible that, by analogy with Mrc1 in yeast, that suppression of DNA replication in response to ER stress via phosphorylation of Claspin serves to minimise conflicts between newly induced UPR stress response genes and ongoing replication in S phase cells.…”