ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress.
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.
Wu
Jun
J
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Rutkowski
D Thomas
DT
Dubois
Meghan
M
Swathirajan
Jayanth
J
Saunders
Thomas
T
Wang
Junying
J
Song
Benbo
B
Yau
Grace D-Y
GD
Kaufman
Randal J
RJ
D051702:Activating Transcription Factor 6 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003433:Crosses, Genetic; D004226:Dithioerythritol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D019426:Integrases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D013439:Sulfhydryl Reagents; D015534:Trans-Activators; D014415:Tunicamycin; D004226:Dithioerythritol; C045073:Cre recombinase; D019426:Integrases