MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy

• Published in: Nature communications Vol. 7; no. 1; p. 12120
• Main Authors: Lange, Stephan, Gehmlich, Katja, Lun, Alexander S., Blondelle, Jordan, Hooper, Charlotte, Dalton, Nancy D., Alvarez, Erika A., Zhang, Xiaoyu, Bang, Marie-Louise, Abassi, Yama A., dos Remedios, Cristobal G., Peterson, Kirk L., Chen, Ju, Ehler, Elisabeth
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.06.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/51; 13/95; 14/19; 631/337/458/1733; 631/443/592/75/74; 631/80/86; 64/110; 692/308; Animals; Cardiomyopathy, Dilated - metabolism; Cell Line; Chlorocebus aethiops; COS Cells; Escherichia coli; Gene Expression Regulation; Heart Failure - etiology; Humanities and Social Sciences; Humans; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; Male; Mice; multidisciplinary; Muscle Proteins - genetics; Muscle Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12120

MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1. In mice deficient for both MLP and CARP the chronic PKCα signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKCα and that chronic uninhibited PKCα activity at the intercalated disc in the absence of functional MLP leads to heart failure. Altered function of the muscle LIM protein (MLP) causes dilated cardiomyopathy in mice and humans. Lange et al . explain the molecular role of MLP in the heart by showing that it affects the signalling complex at the intercalated discs of failing hearts that consists of PKCα, PLCβ1 and CARP by inhibiting PKCα auto-phosphorylation and function.