Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle.

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.

• Authors: Ei Leen Leong, Nyein Thet Khaing, Bruno Cadot, Wei Liang Hong, Serguei Kozlov, Hendrikje Werner, Esther Sook Miin Wong, Colin L Stewart, Brian Burke, Yin Loon Lee
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 32 Issue 2 Pg. 177-191 (01 06 2023) ISSN: 1460-2083 [Electronic] England
• PMID: 35925868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press.

Chemical References

• Microtubule Proteins
• Nuclear Proteins
• Membrane Proteins
• Intermediate Filament Proteins

Topics

• Animals
• Mice
• Microtubule Proteins (metabolism)
• Nuclear Proteins (metabolism)
• Membrane Proteins (genetics)
• Cytoskeleton (genetics, metabolism)
• Nuclear Matrix (genetics)
• Microtubules (metabolism)
• Nuclear Envelope (genetics, metabolism)
• Intermediate Filament Proteins (metabolism)
• Muscle, Striated (metabolism)
• Laminopathies (metabolism)