| First Author | Cloots E | Year | 2024 |
| Journal | EMBO J | Volume | 43 |
| Issue | 5 | Pages | 695-718 |
| PubMed ID | 38177501 | Mgi Jnum | J:346074 |
| Mgi Id | MGI:7609926 | Doi | 10.1038/s44318-023-00015-y |
| Citation | Cloots E, et al. (2024) Activation of goblet-cell stress sensor IRE1beta is controlled by the mucin chaperone AGR2. EMBO J 43(5):695-718 |
| abstractText | Intestinal goblet cells are secretory cells specialized in the production of mucins, and as such are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme-1beta (IRE1beta), a unique sensor in the unfolded protein response (UPR), which is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1beta activity is tuned to mucus folding load remains unknown. We identified the disulfide isomerase and mucin chaperone AGR2 as a goblet cell-specific protein that crucially regulates IRE1beta-, but not IRE1alpha-mediated signaling. AGR2 binding to IRE1beta disrupts IRE1beta oligomerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1beta activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1beta activation. We found that AGR2 mutants lacking their catalytic cysteine, or displaying the disease-associated mutation H117Y, were no longer able to dampen IRE1beta activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1beta endonuclease activity. |
