Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere

Li, Chen, Warren, Derek T., Zhou, Can, De Silva, Shanelle, Wilson, Darren G. S., Garcia-Maya, Mitla, Wheeler, Mathew A., Meinke, Peter, Sawyer, Greta, Ehler, Elisabeth, Wehnert, Manfred, Rao, Li, Zhang, Qiuping and Shanahan, Catherine M. (2024) Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere. Journal of Biological Chemistry, 300 (5). ISSN 0021-9258

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Abstract

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function.

Item Type:	Article
Additional Information:	Funding and additional information: This work was supported by the British Heart Foundation (BHF) [RG/17/2/32808 & RG/F/21/110064 to C. M. S.; PG/11/58/29004 & FS/19/27/3435 & PG/23/11421 to Q. P. Z.]; C. L. was supported by National Natural Science Foundation of China [82071735 to L. R.] and the China Scholarship Council. Work in the Ehler lab was supported by UKRI-MRC (MR/R017050/1) and by the KCL BHF Centre MRes/PhD programme. Funding to pay Open Access publication charges for this article was provided by the BHF.
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Depositing User:	LivePure Connector
Date Deposited:	08 Apr 2024 10:30
Last Modified:	07 May 2024 16:31
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94853
DOI:	10.1016/j.jbc.2024.107254

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