Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice.
Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca(2+) current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.
Hamada
Hiromichi
H
Department of Molecular Embryology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba City, Chiba, Japan.
Suzuki
Masashi
M
Yuasa
Shigeki
S
Mimura
Naoya
N
Shinozuka
Norihiro
N
Takada
Yuki
Y
Suzuki
Misao
M
Nishino
Takashi
T
Nakaya
Haruaki
H
Koseki
Haruhiko
H
Aoe
Tomohiko
T
D000818:Animals; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D013314:Stress, Mechanical
C064459:KDEL receptor; D018000:Receptors, Peptide; D011994:Recombinant Proteins