Wu Jun, Rutkowski D Thomas, Dubois Meghan, Swathirajan Jayanth, Saunders Thomas, Wang Junying, Song Benbo, Yau Grace D-Y, Kaufman Randal J
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Dev Cell. 2007 Sep;13(3):351-64. doi: 10.1016/j.devcel.2007.07.005.
In vertebrates, three proteins--PERK, IRE1alpha, and ATF6alpha--sense protein-misfolding stress in the ER and initiate ER-to-nucleus signaling cascades to improve cellular function. The mechanism by which this unfolded protein response (UPR) protects ER function during stress is not clear. To address this issue, we have deleted Atf6alpha in the mouse. ATF6alpha is neither essential for basal expression of ER protein chaperones nor for embryonic or postnatal development. However, ATF6alpha is required in both cells and tissues to optimize protein folding, secretion, and degradation during ER stress and thus to facilitate recovery from acute stress and tolerance to chronic stress. Challenge of Atf6alpha null animals in vivo compromises organ function and survival despite functional overlap between UPR sensors. These results suggest that the vertebrate ATF6alpha pathway evolved to maintain ER function when cells are challenged with chronic stress and provide a rationale for the overlap among the three UPR pathways.
在脊椎动物中，三种蛋白质——蛋白激酶R样内质网激酶（PERK）、肌醇需求酶1α（IRE1α）和活化转录因子6α（ATF6α）——可感知内质网中的蛋白质错误折叠应激，并启动内质网到细胞核的信号级联反应以改善细胞功能。这种未折叠蛋白反应（UPR）在应激期间保护内质网功能的机制尚不清楚。为了解决这个问题，我们在小鼠中删除了Atf6α。ATF6α对于内质网蛋白伴侣的基础表达既不是必需的，对于胚胎发育或出生后发育也不是必需的。然而，在细胞和组织中，ATF6α都是优化内质网应激期间蛋白质折叠、分泌和降解所必需的，从而促进从急性应激中恢复并耐受慢性应激。尽管UPR传感器之间存在功能重叠，但体内Atf6α基因敲除动物面临的挑战会损害器官功能和生存。这些结果表明，当细胞受到慢性应激挑战时，脊椎动物的ATF6α途径进化以维持内质网功能，并为三种UPR途径之间的重叠提供了理论依据。
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