| First Author | Eletto D | Year | 2014 |
| Journal | Mol Cell | Volume | 53 |
| Issue | 4 | Pages | 562-576 |
| PubMed ID | 24508390 | Mgi Jnum | J:210646 |
| Mgi Id | MGI:5571560 | Doi | 10.1016/j.molcel.2014.01.004 |
| Citation | Eletto D, et al. (2014) Protein disulfide isomerase A6 controls the decay of IRE1alpha signaling via disulfide-dependent association. Mol Cell 53(4):562-76 |
| abstractText | The response to endoplasmic reticulum (ER) stress relies on activation of unfolded protein response (UPR) sensors, and the outcome of the UPR depends on the duration and strength of signal. Here, we demonstrate a mechanism that attenuates the activity of the UPR sensor inositol-requiring enzyme 1alpha (IRE1alpha). A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1alpha activity by direct binding to cysteine 148 in the lumenal domain of the sensor, which is oxidized when IRE1 is activated. PDIA6-deficient cells hyperrespond to ER stress with sustained autophosphorylation of IRE1alpha and splicing of XBP1 mRNA, resulting in exaggerated upregulation of UPR target genes and increased apoptosis. In vivo, PDIA6-deficient C. elegans exhibits constitutive UPR and fails to complete larval development, a program that normally requires the UPR. Thus, PDIA6 activity provides a mechanism that limits UPR signaling and maintains it within a physiologically appropriate range. |
