Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?
Figure 3
Signaling by PERK, IRE1, and ATF6. In an unstressed condition, GRP78, the primary sensor of ER stress binds to transmembrane ER proteins, PERK, IRE1, and ATF6, preventing their activation. The accumulation of unfolded proteins leads to dissociation of GRP78 from PERK, IRE1, and ATF6. GRP78, however, binds to the unfolded protein. GRP78 dissociation leads to PERK and IRE1 oligomerization and trans-autophosphorylation of their cytosolic domains. The active phosphorylated PERK (p-PERK, active) in turn phosphorylates eIF2α (p-eIF2α, inactive), leading to attenuation of global protein synthesis. Under these conditions, selected mRNAs, such as ATF4, are translated, which induces the expression of genes involved in restoring ER homeostasis. ATF4 can activate GADD34, which recruits a phosphatase to dephosphorylate p-PERK and reverse translational attenuation. ER-resident is an inhibitor of PERK. Phosphorylation of IRE1 (p-IRE1) activates its endoribonucleolytic activity, which then excises an intron of the XBP1 mRNA to generate a mature XBP1 mRNA, which then encodes for the active protein, XBP1. The XBP1 protein then translocates into the nucleus and supports the ER stress response. Interaction of p-IRE1 with TRAF2 can elicit the activation of the JNK pathway and caspases leading to apoptosis. GRP78 release from the dimeric ATF6 leads to the translocation of its monomeric form to the Golgi, where it undergoes proteolytic processing by the proteases (S1P and S2P). The cleaved ATF6 then translocates to the nucleus where it activates the ERSR genes and chaperones. Alternatively, CHOP/GADD153 can be activated by ATF4, ATF6, or XBP1, which promotes apoptosis by decreasing the levels of antiapoptotic Bcl-2 in the cell. The dotted arrows denote translocation. XBP1 (a) denotes the mature XBP1 mRNA, while XBP1p denotes the protein product of XBP1 (a). The “+” sign signifies activation.
