Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle.
Animals
Mice
Microtubule Proteins
/ metabolism
Nuclear Proteins
/ metabolism
Membrane Proteins
/ genetics
Cytoskeleton
/ genetics
Nuclear Matrix
/ genetics
Microtubules
/ metabolism
Nuclear Envelope
/ genetics
Intermediate Filament Proteins
/ metabolism
Muscle, Striated
/ metabolism
Laminopathies
/ metabolism
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
06 01 2023
06 01 2023
Historique:
received:
02
12
2021
revised:
27
07
2022
accepted:
29
07
2022
pubmed:
5
8
2022
medline:
18
1
2023
entrez:
4
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35925868
pii: 6655857
doi: 10.1093/hmg/ddac179
pmc: PMC9840208
doi:
Substances chimiques
Microtubule Proteins
0
Nuclear Proteins
0
Membrane Proteins
0
Intermediate Filament Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
177-191Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
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