Cell News—A new class of unfolded protein response inhibitors

Electron micrograph of rough endoplasmic reticulum from Chapter 5 of 'The Cell, 2nd Ed.' by Don W. Fawcett M.D. Image sourced from The Cell Image Library.

Electron micrograph of rough endoplasmic reticulum, where UPR begins, from Chapter 5 of ‘The Cell, 2nd Ed.’ by Don W. Fawcett M.D. Image sourced from The Cell Image Library.

When unfolded or misfolded proteins accumulate in the cell’s endoplasmic reticulum (ER) an unfolded protein response (UPR) is triggered to mitigate the potential damage. The UPR has been implicated in a number of neurodegenerative diseases, and inhibiting the process could ameliorate Creutzfeldt-Jakob disease, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. And now a new class of UPR inhibitors, Ceapins, has been discovered and reported in two new papers by Ciara Gallagher, a postdoc and ASCB member, and colleagues in ASCB President Peter Walter’s lab at the University of California, San Francisco. The two papers describe the Ceapins’ targets and mechanism of action. Ceapins, named from the Irish verb ceap,” meaning to trap,” are a class of pyrazole amides that selectively block ATF6α, one of the three branches of UPR activation. Ceapins inhibit ATF6α signaling by trapping it in ER foci that do not exit the ER, and washout restores normal ATF6α localization. With this discovery, all three branches of the UPR can now be pharmacologically inhibited individually or in combination.

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