Nuclear lamina, along with the cytoskeleton, serves as a transducer of mechanical and chemical signals from the exterior of the cell and the cytoplasm to the chromatin and hence governs gene expression. Here, we show that Hepatitis C Virus (HCV) alters the morphology and the stiffness of nuclei by down-regulating lamin-A,C, thereby disrupting the nuclear lamina. The nuclei of liver cell line expressing HCV proteins have larger projected area and volume than those of normal liver cells. Reduction in the modulus of elasticity of the nuclear envelope and a simultaneous increase in actin pre-stress were identified as the causes for the observed changes in nuclear morphology with the help of computational modeling. These predictions were validated biomechanically by showing that liver cells expressing HCV proteins possessed enhanced cellular stiffness and reduced nuclear stiffness, indicating increased tension in cortical actin and reduced elastic modulus of the nucleus. Concomitantly, cells expressing HCV proteins showed down-regulation of lamin-A,C and up-regulation of actin, corroborating the predictions of the model. When exposed to shear stress comparable to that in liver, the nuclei of liver cells expressing HCV proteins became increasingly elliptical over time. Taken together, our results show a possible deregulation of cellular mechanobiology by HCV through disruption of the nuclear lamina, thereby rendering the nucleus susceptible to shear stress due to flow. Altered gene expression and defective mechano-transduction through changes in nuclear mechanics could contribute significantly to HCV pathogenesis.
Most parts of this experimental work, except for the response to flow, are available in our publication.