IRE1α and PERK are two different ER transmembrane proteins that homo-oligomerize through an ER lumenal domain that senses unfolded proteins (Aragon et al., 2009; Credle et al., 2005; Gardner and Walter, 2011; Zhou et al., 2006). Both ER stress sensors have serine/threonine kinase activities on their cytosolic face. For both PERK and IRE1α, homo-oligomerization of ER lumenal domains juxtaposes their respective cytosolic kinase domains, and they consequently trans-autophosphorylate. For PERK, trans-autophosphorylation is a potentiating step that causes the kinase to subsequently phosphorylate the translation initiation factor, eIF2α, causing translational attenuation. We noted that forced dimerization using a chemical dimerizer of a FK506 binding protein-PERK eIF2α kinase construct is sufficient to induce TXNIP mRNA, without upstream ER stress (Figure S3B and C).
