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Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

2007; Rockefeller University Press; Volume: 204; Issue: 5 Linguagem: Inglês

10.1084/jem.20070145

1540-9538

Blanche Schroen, Joost J. Leenders, Arie van Erk, A. Bertrand, Mirjam van Loon, Rick E. van Leeuwen, Nard Kubben, Rudy F. Duisters, Mark W.M. Schellings, Ben Janssen, Jacques Debets, Michael Schwake, Morten A. Høydal, Stéphane Heymans, Paul Säftig, Yigal M. Pinto,

Signaling Pathways in Disease

The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also find LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated β-catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect. Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.