Description:

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:

Megan King, PhD
Associate Professor of Cell Biology
Yale University

The ability of the LINC complex to transmit mechanical forces generated by the cytoplasmic cytoskeleton directly to the nuclear lamina has long suggested its potential to act as a mechanotransducer. While it is clear that the LINC complex transmits forces from the cytoskeleton onto the nuclear lamina, if remains unknown whether this force transmission per se directly impacts gene regulation. Moreover, the signaling pathways and physiological contexts in which such a direct force transmission and mechanotransduction mechanism play a role remain poorly defined. Leveraging mouse models of LINC complex ablation (Sun2-/- and Sun1-/-/Sun2-/), we have uncovered new evidence to suggest that the LINC complex plays a critical role in several mechanosensitive signaling pathways, particularly those involving TGF- and SMADs. We observe an increase in cytoskeletal contractility in cells lacking LINC complexes coincident with nuclear accumulation of several mechanosensitive transcription factors including phosphorylated SMADs, MKL/MRTF, and YAP. Surprisingly, gene targets of these pathways remain in the repressed state, suggesting that the LINC complex positively influences the ability of these pathways to drive gene activation with the nucleoplasm. Intriguingly, LINC complex ablated cells show elevated levels of MAN1 at the nuclear lamina; MAN1 is an integral inner nuclear membrane protein of the LEM domain family and an established inhibitor of gene activation by SMADs. Taken together these findings support a model in which the LINC complex positively influences SMAD signaling by remodeling the nuclear lamina. The relevance of these findings is underscored by our observation that loss of SUN2, although sufficient to drive cardiac hypertrophy in mice, prevents the increased expression of extracellular matrix proteins and interstitial fibrosis typically coincident with hypertrophic disease. As the TGF- pathway is a major driver of pathological fibrosis, we suggest that mechanotransduction through the LINC complex is required to license activation of TGF- targets within the nucleoplasm.