Professor Teresita Padilla-Benavides of Wesleyan University

"CSRP2 a novel copper binding protein that regulates myoblast proliferation"

Copper (Cu) is a vital micronutrient that is imperative for the proliferation and development of mammalian cells. Surplus of Cu is toxic to cells, so a broad network of transporters, chaperones, and regulators maintains the homeostasis of Cu. Failure in the homeostatic machinery of Cu confers various muscular degradation pathologies such as Menkes and Wilson's disease (1). The Metal Regulatory Transcription Factor 1 (MTF1) is a key regulator of the cellular Cu network that ensures metal homeostasis (2, 3). In addition, we found that MTF1 is also necessary for the differentiation of primary myoblasts derived from mouse satellite cells (4). MTF1 does not act alone, immunoprecipitation assays coupled to mass spectrometry, suggested that MTF1 interacts with chromatin remodeling proteins and a novel group of Cu-binding proteins present in myoblasts. Among these interactors, CSRP2 has emerged as a novel Cu-binding protein with redox potential determined by cyclic voltammetry analyses. Recombinant purified CSRP2 protein binds at least two Cu ions which confers the redox potential to the protein. We are characterizing the functional properties of CSRP2, as a potential component of a novel Cu-dependent regulatory network which orchestrates metal homeostasis and the development of skeletal muscles in vitro. RNA-seq and Cut & Run showed that CSRP2 regulates the expression of genes required for the proliferation of primary myoblasts. Our studies pose CSRP2 as a potential new targets for the treatments of Cu-related myopathies and muscular phenotypes in patients with Menkes or Wilson’s diseases.

References
1. Maung, M. T., Carlson, A., Olea-Flores, M., Elkhadragy, L., Schachtschneider, K. M., Navarro-Tito, N., and Padilla-Benavides, T. (2021) The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. Faseb J 35, e21810
2. Chen, X., Hua, H., Balamurugan, K., Kong, X., Zhang, L., George, G. N., Georgiev, O., Schaffner, W., and Giedroc, D. P. (2008) Copper sensing function of Drosophila metal-responsive transcription factor-1 is mediated by a tetranuclear Cu(I) cluster. Nucleic Acids Res 36, 3128-3138
3. Giedroc, D. P., Chen, X., and Apuy, J. L. (2001) Metal response element (MRE)-binding transcription factor-1 (MTF-1): structure, function, and regulation. Antioxidants & redox signaling 3, 577-596
4. Tavera-Montanez, C., Hainer, S. J., Cangussu, D., Gordon, S. J. V., Xiao, Y., Reyes-Gutierrez, P., Imbalzano, A. N., Navea, J. G., Fazzio, T. G., and Padilla-Benavides, T. (2019) The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper. FASEB J 33, 14556-14574