The Unfolded Protein Response: An Overview

Abstract

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH₂ domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.

Keywords: ATF6; ERAD; IRE1; PERK; RIDD; UPR; inactivation.

Figure 1

The unfolded protein response. The Ire1 pathway of the unfolded protein response: (A) Ire1-bound BiP/Kar2 (yellow) is released from the luminal domain of Ire1 when unfolded proteins accumulate leading to the oligomerisation and trans-autophosphorylation of Ire1 monomers. (B) Unspliced HAC1/XBP1 mRNA is spliced by the endoribonuclease domain of Ire1 and the two exons ligated together by tRNA ligase (pink). (C) The HAC1ⁱ/XBP1^s mRNA is then translated into an active protein. (D) The newly synthesised protein then enters the nucleus and binds to the promoter regions of target genes.

Figure 2

The PERK pathway of the unfolded protein response. (A) BiP bound to the luminal domain of PERK dissociates when unfolded proteins accumulate allowing oligomerisation and phosphorylation of the PERK monomers. (B) Phosphorylated PERK then phosphorylates eIF2 on its α subunit at S51. (C) Phosphorylated eIF2α interferes with ribosomal translation of mRNA and causes downstream ORFs to be translated, such as ATF4. (D) ATF4 induces expression of ATF3 and CHOP. (E) ATF3 binds to the promoter region of GADD34 which activates a protein phosphatase which dephosphorylates eIF2α. (F) CHOP induces ER stress-induced apoptosis.

Figure 3

Signal transduction by ATF6 in the UPR. (A) In unstressed conditions, binding of BiP to the COOH terminal ER luminal domain of the type II transmembrane protein ATF6 keeps ATF6 inactive. The NH₂ terminal domain is located in the cytosol. (B) Under ER stress unfolded proteins accumulate leading to dissociation of BiP from ATF6. ATF6 then translocates to the Golgi complex from the ER. (C) ATF6 is first cleaved by S1P in the transmembrane domains and then by S2P in the cytosolic domain near the ER membrane to release the NH₂-terminal domain. (D) The NH₂-terminal domain migrates to the nucleus where it induces gene expression.