The coiled-coil domain of MURC/cavin-4 is involved in membrane trafficking of caveolin-3 in cardiomyocytes

Abstract

Muscle-restricted coiled-coil protein (MURC), also referred to as cavin-4, is a member of the cavin family that works cooperatively with caveolins in caveola formation and function. Cavins are cytoplasmic proteins with coiled-coil domains and form heteromeric complexes, which are recruited to caveolae in cells expressing caveolins. Among caveolins, caveolin-3 (Cav3) is exclusively expressed in muscle cells, similar to MURC/cavin-4. In the heart, Cav3 overexpression contributes to cardiac protection, and its deficiency leads to progressive cardiomyopathy. Mutations in the MURC/cavin-4 gene have been identified in patients with dilated cardiomyopathy. In the present study, we show the role of MURC/cavin-4 as a caveolar component in the heart. In H9c2 cells, MURC/cavin-4 was localized at the plasma membrane, whereas a MURC/cavin-4 mutant lacking the coiled-coil domain (ΔCC) was primarily localized to the cytoplasm. ΔCC bound to Cav3 and impaired membrane localization of Cav3 in cardiomyocytes. Additionally, although ΔCC did not alter Cav3 mRNA expression, ΔCC decreased the Cav3 protein level. MURC/cavin-4 and ΔCC similarly induced cardiomyocyte hypertrophy; however, ΔCC showed higher hypertrophy-related fetal gene expression than MURC/cavin-4. ΔCC induced ERK activation in cardiomyocytes. Transgenic mice expressing ΔCC in the heart (ΔCC-Tg mice) showed impaired cardiac function accompanied by cardiomyocyte hypertrophy and marked interstitial fibrosis. Hearts from ΔCC-Tg mice showed a reduction of the Cav3 protein level and activation of ERK. These results suggest that MURC/cavin-4 requires its coiled-coil domain to target the plasma membrane and to stabilize Cav3 at the plasma membrane of cardiomyocytes and that MURC/cavin-4 functions as a crucial caveolar component to regulate cardiac function.

The FOXK1-CCDC43 Axis Promotes the Invasion and Metastasis of Colorectal Cancer Cells

“…To date, more than 140 genes contain the coiled-coil domain, but their functions are unknown in many cases (http://www.genecards.org/). Previous studies have shown that approximately 40 CCDC genes are associated with diseases, including various metabolic diseases [4], cancers [5][6][7], mitochondrial disease [8], epigenetic disease [9] and heart disease [10]. The abnormal expression of CCDC containing proteins in nasopharyngeal carcinoma [7], prostate cancer [5], pancreatic cancer [6], gastric cancer [9], breast cancer [11] and colorectal cancer (CRC).…”

Effect of atorvastatin on cardiomyocyte hypertrophy through suppressing MURC induced by volume overload and cyclic stretch

“…However, the specific inhibitors of JNK and p38 did not affect the stretch‐induced MURC protein expression. Naito et al noted that MURC mutant lacking coiled‐coil domain enhanced ERK activation . In another study, MURC modulated cardiomyocyte hypertrophy occurred through ERK activation .…”

“…A recent study showed that MURC could interact with Cavin‐1, Cavin‐2 and Cavin‐3 to form caveolae. Overexpression of MURC swelled the caveolae but was not crucial to caveolae formation . MURC was found to be expressed in vascular smooth muscle cells, skeletal muscle cells and cardiomyocytes .…”

MURC deficiency in smooth muscle attenuates pulmonary hypertension

“…Total RNA was converted to cDNA using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Synthesized cDNA was analysed by kinetic real-time PCR using Takara PCR Thermal Cycler Dice (Takara Bio) with Platinum SYBR Green qPCR Super Mix (Invitrogen)203456. The primer sequences used were as follows: mouse Murc forward primer (5′-ACAGTCACACAGCAATACGGGCTA-3′) and mouse Murc reverse primer (5′-TTCTCGGGCAGGCTTCTGTCTTTA-3′); and mouse GAPDH forward primer (5′-TTGTGATGGGTGTGAACCACGAGA-3′) and mouse GAPDH reverse primer (5′-CATGAGCCCTTCCACAATGCCAAA-3′).…”

“…Microtome sections were examined under a H-7100 transmission electron microscope (HITACHI, Tokyo, Japan) and photographed at a magnification of × 40,000 or × 20,000. Caveolae were identified by their characteristic flask shape and location at or near the plasma membrane3456.…”