Functional properties of the titin/connectin-associated proteins, the muscle-specific RING finger proteins (MURFs), in striated muscle
The efficient functioning of striated muscle is dependent upon the proper alignment and coordinated activities of several cytoskeletal networks including myofibrils, microtubules, and intermediate filaments. However, the exact molecular mechanisms dictating their cooperation and contributions during muscle differentiation and maintenance remain unknown. Recently, the muscle specific RING finger (MURF) family members have established themselves as excellent candidates for linking myofibril components (including the giant, multi-functional protein, titin/connectin), with microtubules, intermediate filaments, and nuclear factors. MURF-1, the only family member expressed throughout development, has been implicated in several studies as an ubiquitin ligase that is upregulated in response to multiple stimuli during muscle atrophy. Cell culture studies suggest that MURF-1 specifically has a role in maintaining titin M-line integrity and yeast two-hybrid studies point toward its participation in muscle stress response pathways and gene expression. MURF-2 is developmentally down-regulated and is assembled at the M-line region of the sarcomere and with microtubules. Functionally, its expression is critical for maintenance of the sarcomeric M-line region, specific populations of stable microtubules, desmin and vimentin intermediate filaments, as well as for myoblast fusion and differentiation. A recent study also links MURF-2 to a titin kinase-based protein complex that is reportedly activated upon mechanical signaling. Finally, MURF-3 is developmentally upregulated, associates with microtubules, the sarcomeric M-line (this report) and Z-line, and is required for microtubule stability and myogenesis. Here, we focus on the biochemical and functional properties of this intriguing family of muscle proteins, and discuss how they may tie together titin-mediated myofibril signaling pathways (perhaps involving the titin kinase domain), biomechanical signaling, the muscle stress response, and gene expression.
KeywordsCardiac Myocytes Ubiquitin Ligase Skeletal Muscle Atrophy Nebulin Muscle Gene Expression
This article was written in memory of Dr. Koscak Maruyama. The authors would like to thank Siegfried Labeit for providing MURF-3 cDNA and for insightful editorial comments, and Sarah Mount-Patrick and Catherine Schwach for assistance in preparing the figures. This study was funded by grants from the NIH (HL63926) and (HL57461) to C.C.G., the American Heart Association (0435316N) to A.S.M., and a HHMI grant (71195-521304) to the University of Arizona for undergraduate biology research funding to C.N.P.
- Bang ML, Centner T, Fornoff F, Geach A, Gotthardt M, McNabb M, Witt C, Labeit D, Gregorio CC, Granzier H, Labeit S, (2001) The complete gene sequence of titin, expression of an unusual ∼ ∼700 kDa titin isoform and its interaction with obscurin identify a novel Z-line to I-band linking systemCirc Res 89: 1065–1072PubMedGoogle Scholar
- Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ, (2001) Identification of ubiquitin ligases required for skeletal muscle atrophyScience 294: 1704–1708CrossRefPubMedGoogle Scholar
- Gregorio CC, Trombitas K, Centner T, Komerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Hermann B, Granzier H, Sorimachi H, Labeit S, (1998) The NH2 terminus of titin spans the Z-disc: its interaction with a novel 19-kDa ligand (T-cap) is required for sarcomeric integrityJ Cell Biol 143: 1013–1027CrossRefPubMedGoogle Scholar
- Lange S, Xiang F, et al. (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science: ScienceExpressGoogle Scholar
- McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC, (2002) Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1J Cell Biol 157: 125–136CrossRefPubMedGoogle Scholar
- McElhinny AS, Perry CN, Witt C, Labeit S, Gregorio CC, (2004) Muscle specific RING finger-2 (MURF-2) has multiple subcellular localizations and is required for microtubule, intermediate filament, and sarcomeric M-line maintenance in striated muscleJ Cell Sci 117: 3175–3188CrossRefPubMedGoogle Scholar
- Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K, (1995) Muscle-specific calpain responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequenceJ Biol Chem 270: 31158–31162CrossRefPubMedGoogle Scholar