Roles for endoplasmic reticulum-associated degradation and the novel endoplasmic reticulum stress response gene Derlin-3 in the ischemic heart.
BACKGROUND
Stresses, such as ischemia, impair folding of nascent proteins in the rough endoplasmic reticulum (ER), activating the unfolded protein response, which restores efficient ER protein folding, thus leading to protection from stress. In part, the unfolded protein response alleviates ER stress and cell death by increasing the degradation of terminally misfolded ER proteins via ER-associated degradation (ERAD). ERAD is increased by the ER stress modulator, activating transcription factor (ATF)6, which can induce genes that encode components of the ERAD machinery.


OBJECTIVE
Recently, it was shown that the mouse heart is protected from ischemic damage by ATF6; however, ERAD has not been studied in the cardiac context. A recent microarray study showed that the Derlin-3 (Derl3) gene, which encodes an important component of the ERAD machinery, is robustly induced by ATF6 in the mouse heart.


RESULTS
In the present study, activated ATF6 induced Derl3 in cultured cardiomyocytes, and in the heart, in vivo. Simulated ischemia (sI), which activates ER stress, induced Derl3 in cultured myocytes, and in an in vivo mouse model of myocardial infarction, Derl3 was also induced. Derl3 overexpression enhanced ERAD and protected cardiomyocytes from simulated ischemia-induced cell death, whereas dominant-negative Derl3 decreased ERAD and increased simulated ischemia-induced cardiomyocyte death.


CONCLUSIONS
This study describes a potentially protective role for Derl3 in the heart, and is the first to investigate the functional consequences of enhancing ERAD in the cardiac context.
Belmont
Peter J
PJ
The SDSU Heart Institute and the Department of Biology, San Diego State University, San Diego, CA 92182, USA.
Chen
Wenqiong J
WJ
San Pedro
Matthew N
MN
Thuerauf
Donna J
DJ
Gellings Lowe
Nicole
N
Gude
Natalie
N
Hilton
Brett
B
Wolkowicz
Roland
R
Sussman
Mark A
MA
Glembotski
Christopher C
CC
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014415:Tunicamycin / Q000494:pharmacology
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D008565:Membrane Proteins; D035683:MicroRNAs; D014415:Tunicamycin