Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna -mutant striated muscle - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Human Molecular Genetics Année : 2022

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

Ei Leen Leong
  • Fonction : Auteur
Nyein Thet Khaing
  • Fonction : Auteur
Wei Liang Hong
  • Fonction : Auteur
Serguei Kozlov
  • Fonction : Auteur
Hendrikje Werner
  • Fonction : Auteur
Esther Sook Miin Wong
  • Fonction : Auteur
Colin Stewart
  • Fonction : Auteur
Brian Burke
Yin Loon Lee

Résumé

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.

Dates et versions

hal-03820020 , version 1 (18-10-2022)

Identifiants

Citer

Ei Leen Leong, Nyein Thet Khaing, Bruno Cadot, Wei Liang Hong, Serguei Kozlov, et al.. Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna -mutant striated muscle. Human Molecular Genetics, 2022, ⟨10.1093/hmg/ddac179⟩. ⟨hal-03820020⟩
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