Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Sep 2

PMID 15340063

Citations 70

Authors

Hiromichi Hamada

Masashi Suzuki

Shigeki Yuasa

Naoya Mimura

Norihiro Shinozuka

Yuki Takada

Misao Suzuki

Takashi Nishino

Haruaki Nakaya

Haruhiko Koseki

Tomohiko Aoe

Affiliations

Soon will be listed here.

Abstract

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.

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References

Massart P, Donckier J, Kyselovic J, GODFRAIND T, Heyndrickx G, Wibo M . Carvedilol and lacidipine prevent cardiac hypertrophy and endothelin-1 gene overexpression after aortic banding. Hypertension. 1999; 34(6):1197-201. DOI: 10.1161/01.hyp.34.6.1197. View

Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding H . Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000; 287(5453):664-6. DOI: 10.1126/science.287.5453.664. View

Reimold A, Etkin A, Clauss I, Perkins A, Friend D, Zhang J . An essential role in liver development for transcription factor XBP-1. Genes Dev. 2000; 14(2):152-7. PMC: 316338. View

Ross Jr J . Dilated cardiomyopathy: concepts derived from gene deficient and transgenic animal models. Circ J. 2002; 66(3):219-24. DOI: 10.1253/circj.66.219. View

Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K . ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002; 16(11):1345-55. PMC: 186318. DOI: 10.1101/gad.992302. View

Taxis C, Vogel F, Wolf D . ER-golgi traffic is a prerequisite for efficient ER degradation. Mol Biol Cell. 2002; 13(6):1806-18. PMC: 117605. DOI: 10.1091/mbc.01-08-0399. View

Yussman M, Toyokawa T, Odley A, Lynch R, Wu G, Colbert M . Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med. 2002; 8(7):725-30. DOI: 10.1038/nm719. View

Haynes C, Caldwell S, Cooper A . An HRD/DER-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport. J Cell Biol. 2002; 158(1):91-101. PMC: 2173032. DOI: 10.1083/jcb.200201053. View

Shen J, Chen X, Hendershot L, Prywes R . ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell. 2002; 3(1):99-111. DOI: 10.1016/s1534-5807(02)00203-4. View

10.

Kaufman R . Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002; 110(10):1389-98. PMC: 151822. DOI: 10.1172/JCI16886. View

11.

Ruwhof C, van der Laarse A . Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res. 2000; 47(1):23-37. DOI: 10.1016/s0008-6363(00)00076-6. View

12.

Li C, Xu Q . Mechanical stress-initiated signal transductions in vascular smooth muscle cells. Cell Signal. 2000; 12(7):435-45. DOI: 10.1016/s0898-6568(00)00096-6. View

13.

Kopito R, Ron D . Conformational disease. Nat Cell Biol. 2000; 2(11):E207-9. DOI: 10.1038/35041139. View

14.

Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho J . Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest. 2001; 107(5):585-93. PMC: 199427. DOI: 10.1172/JCI11476. View

15.

Suzuki M, Li R, Miki T, Uemura H, Sakamoto N, Tamagawa M . Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ Res. 2001; 88(6):570-7. DOI: 10.1161/01.res.88.6.570. View

16.

Patil C, Walter P . Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr Opin Cell Biol. 2001; 13(3):349-55. DOI: 10.1016/s0955-0674(00)00219-2. View

17.

Bence N, Sampat R, Kopito R . Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001; 292(5521):1552-5. DOI: 10.1126/science.292.5521.1552. View

18.

Yamamoto K, Fujii R, TOYOFUKU Y, Saito T, Koseki H, Hsu V . The KDEL receptor mediates a retrieval mechanism that contributes to quality control at the endoplasmic reticulum. EMBO J. 2001; 20(12):3082-91. PMC: 150210. DOI: 10.1093/emboj/20.12.3082. View

19.

Harding H, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H . Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001; 7(6):1153-63. DOI: 10.1016/s1097-2765(01)00264-7. View

20.

Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R . An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 2001; 105(7):891-902. DOI: 10.1016/s0092-8674(01)00407-x. View