Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

Figure 1

ER stress and activation of the UPR signalling pathways. Accumulation of misfolded or unfolded protein aggregates in the ER lumen, a condition known as ER stress, leads to activation of three ER transmembrane proteins, PERK, IRE1, and ATF6. GRP78, a ubiquitous ER chaperone that is normally bound to these ER stress sensors and keeps them inactive, dissociates from them in order to assist with the folding of proteins in the ER lumen. However, this dissociation leads to activation of the 3 UPR pathways. (1) PERK homodimerization and autophosphorylation results in the subsequent phosphorylation of the α subunit of eIF2 which by inhibiting global protein synthesis reduces the ER protein load. ATF4 expression, however, increases upon eIF2α phosphorylation which translocates to the nucleus allowing for transcription of UPR target genes by binding to the UPR response element (UPRE). These genes include CHOP, a proapoptotic transcription factor that results in cell death if ER stress conditions persist, and GADD34, which acts as a negative regulator of the PERK pathway by dephosphorylating eIF2α. (2) IRE1 is activated in a similar manner to PERK by homodimerization and autophosphorylation. Additionally, interaction of misfolded or unfolded proteins with the luminal domain of IRE1 can also further promote its activation. XBP1 mRNA is an IRE1 substrate that undergoes splicing to produce XBP1s, encoding a transcription factor that can lead to upregulation of ER chaperones and other UPR target genes. (3) ATF6 activation leads to its translocation to the Golgi where it is sequentially cleaved by site 1 and site 2 proteases. This leads to the release of the N-terminal ATF6 fragment which translocates to the nucleus, binds to the ER stress response element (ERSE) thereby activating UPR target genes.