bip binding to the er-stress sensor ire1 tunes the homeostatic behavior of the unfolded protein response毕普绑定er-stress传感器ire1曲调的稳态行为展开的蛋白质反应.pdfVIP

BiP Binding to the ER-Stress Sensor Ire1 Tunes the Homeostatic Behavior of the Unfolded Protein Response 1,2 1 ´ ´ 1,2¤a 1,2¤b 1 David Pincus , Michael W. Chevalier , Tomas Aragon , Eelco van Anken , Simon E. Vidal , Hana El-Samad1*, Peter Walter1,2 1 Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California, United States of America, 2 Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California, Unites States of America Abstract The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and