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Ablation of SUN2-containing LINC complexes drives cardiac hypertrophy without interstitial fibrosis
- Source :
- Molecular Biology of the Cell
- Publication Year :
- 2019
- Publisher :
- American Society for Cell Biology (ASCB), 2019.
-
Abstract
- The cardiomyocyte cytoskeleton, including the sarcomeric contractile apparatus, forms a cohesive network with cellular adhesions at the plasma membrane and nuclear-cytoskeletal linkages (LINC complexes) at the nuclear envelope. Human cardiomyopathies are genetically linked to the LINC complex and A-type lamins, but an full understanding of disease etiology in these patients is lacking. Here we show SUN2-null mice display cardiac hypertrophy coincident with enhanced AKT/MAPK signaling, as has been described previously for mice lacking A-type lamins. Surprisingly, in contrast to lamin A/C-null mice, SUN2-null mice fail to show coincident fibrosis or upregulation of pathological hypertrophy markers. Thus, cardiac hypertrophy is uncoupled from pro-fibrotic signaling in this mouse model, which we tie to a requirement for the LINC complex in productive TGFβ signaling. In the absence of SUN2, we detect elevated levels of the integral inner nuclear membrane protein MAN1, an established negative regulator of TGFβ signaling, at the nuclear envelope. We suggest that A-type lamins and SUN2 play antagonistic roles in the modulation of pro-fibrotic signaling through opposite effects on MAN1 levels at the nuclear lamina, suggesting a new perspective on disease etiology.
- Subjects :
- Sarcomeres
Cell Nucleus Shape
Integrins
MAP Kinase Signaling System
Nuclear Envelope
LINC complex
Telomere-Binding Proteins
Cardiomegaly
030204 cardiovascular system & hematology
Biology
Muscle hypertrophy
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Transforming Growth Factor beta
Fibrosis
Cell Adhesion
medicine
Animals
Cytoskeleton
Molecular Biology
Protein kinase B
030304 developmental biology
Mice, Knockout
0303 health sciences
Chemistry
Myocardium
Membrane Proteins
Articles
Cell Biology
medicine.disease
Cell biology
DNA-Binding Proteins
Mice, Inbred C57BL
Cell Biology of Disease
Multiprotein Complexes
Nuclear lamina
Proto-Oncogene Proteins c-akt
Gene Deletion
030217 neurology & neurosurgery
Lamin
Subjects
Details
- ISSN :
- 19394586 and 10591524
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Molecular Biology of the Cell
- Accession number :
- edsair.doi.dedup.....e8f019f7dedf25aa0ac343a4be0ee6e9