Intracellular Signaling by the Unfolded Protein Response

Abstract

The unfolded protein response (UPR) is an intracellular signaling pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). UPR activation triggers an extensive transcriptional response, which adjusts the ER protein folding capacity according to need. As such, the UPR constitutes a paradigm of an intracellular control mechanism that adjusts organelle abundance in response to environmental or developmental clues. The pathway involves activation of ER unfolded protein sensors that operate in parallel circuitries to transmit information across the ER membrane, activating a set of downstream transcription factors by mechanisms that are unusual yet rudimentarily conserved in all eukaryotes. Recent results shed light on the mechanisms by which unfolded proteins are sensed in the ER and by which the unfolded protein signals are relayed and integrated to reestablish homeostasis in the cell's protein folding capacity or-if this cannot be achieved-commit cells to apoptosis.

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

“…Protein folding in the ER is disrupted by numerous insults, including pharmacological perturbations, genetic mutation of ER chaperones or their client proteins, elevated expression of proteins that transit the endomembrane system, viral infection, alterations in Ca 2+ or redox status, differentiation of cells that secrete large amounts of proteins, and decreases as well as increases in available nutrients. The accumulation of unfolded or misfolded proteins in the ER lumen activates the UPR (Schroder and Kaufman 2005;Bernales et al 2006). The UPR is signaled through three ER transmembrane proteins: inositol-requiring enzyme 1α (IRE1α), PKR (dsRNA-activated protein kinase)-related ER protein kinase (PERK), and activating TF 6α (ATF6α) Walter and Ron 2011).…”

“…ER homeostasis is disrupted by a number of insults that cause the accumulation of unfolded or misfolded proteins in the ER lumen, thereby activating the unfolded protein response (UPR) (Schroder and Kaufman 2005;Bernales et al 2006). The UPR has outputs designed to couple the ER protein-folding capacity with demand so that the cell can survive and function.…”

Autocrine motility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release

“…This coordinated biochemical response to the accumulation of unfolded and/or misfolded proteins within the ER is termed the unfolded protein response (UPR). 4 Induction of the UPR occurs when the presence of unfolded proteins in the ER exceeds the capacity of the ER to correctly fold these proteins. UPR is associated with a number of normal biological processes, such as induction of antibody production in B cells, as well as with disease states in which it disrupts cell function and induces cell death.…”

Endoplasmic reticulum stress-induced cell death mediated by the proteasome

“…Activation of these molecules results in the inhibition of translation (PERK), upregulation of molecular chaperones (ATF6), and upregulation of ERAD activity (IRE1). 5,6 As a consequence, the ER experiences a reduction in protein folding burden while increasing folding and quality control capacity. If a cell fails to achieve homeostasis after fully activating the UPR and its associated ERAD activity, the cell initiates programmed cell death.…”