Leong, E. L., Khaing, N. T., Cadot, B., Hong, W. L., Kozlov, S., Werner, H., Wong, E. S. M., Stewart, C. L., Burke, B., & Lee, Y. L. (2022). Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle. Human Molecular Genetics, 32(2), 177–191. https://doi.org/10.1093/hmg/ddac179
Abstract:
Abstract
Mutations in LMNA, the gene encoding A-type lamins, cause laminopathies—diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear envelope (NE) such that the nucleus becomes more prone to mechanical damage. The latter model requires a conduit for force transmission to the nucleus. NE-associated Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes are one such pathway. Using clustered regularly interspaced short palindromic repeats to disrupt the Nesprin-1 KASH (Klarsicht, ANC-1, Syne Homology) domain, we identified this LINC complex protein as the predominant NE anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. Loss of Nesprin-1 LINC complexes resulted in loss of microtubule cytoskeleton proteins at the nucleus and changes in nuclear morphology and positioning in striated muscle cells, but with no overt physiological defects. Disrupting the KASH domain of Nesprin-1 suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. Nesprin-1 LINC complexes thus represent a potential therapeutic target for striated muscle laminopathies.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Individual Research Grant
Grant Reference no. : NMRC/OFIRG/0052/2017
This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Individual Research Grant
Grant Reference no. : MOH-000252
This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Individual Research Grant COVID19 Top-up
Grant Reference no. : MOH-000796
This research / project is supported by the National Medical Research Council (NMRC) - Translational Clinical Research
Grant Reference no. : NMRC/TCR/006-NUHS/2013
This research is supported by core funding from: BMRC
Grant Reference no. : N/A
This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Young Individual Research Grant
Grant Reference no. : MOH-OFYIRG18nov-0017
This research / project is supported by the National Medical Research Council (NMRC) - Open Fund - Young Individual Research Grant COVID19 Top-up
Grant Reference no. : MOH-COVID19TUG21-0146
This research / project is supported by the A*STAR - Career Development Award (CDA)
Grant Reference no. : 202D800026
This research / project is supported by the A*STAR - Accelerate Gap
Grant Reference no. : ACCL/19-GAP042-R20H
This research / project is supported by the National Research Foundation - Central Gap
Grant Reference no. : NRF2020NRF-CG001-036