Nuclear membrane deformation via progerin clustering.

Abstract

The lamina, a structural network of lamin proteins, maintains the shape of the nuclear membrane and is involved in its functions. Lamina is also known to affect gene expression regulation by interacting with chromatin. Therefore, if there is an abnormality in the lamin protein, various diseases are caused. One of the typical diseases caused by lamin defects is premature aging, called Hutchinson-Gilford progeria syndrome (HGPS). HGPS is believed to be caused by progerin generated through alternative splicing of pre-lamin A. In HGPS, progerin is incorporated into the lamina, consequently causing severe nuclear membrane deformation. However, it is still unclear how progerin induces nuclear deformation. Here, we generated a cell line that conditionally induced progerin and observed the process of nuclear membrane deformation in real-time using super-resolution fluorescence imaging. Unlike normal lamin proteins, we found progerin is not evenly distributed in the lamina but formed clusters and confirmed that farnesylation of the progerin c-terminus domain is crucial to the clustering. Moreover, we demonstrated the nuclear membrane deformation by the progerin cluster through invagination rather than the protrusion. Based on the novel layered structure that progerin displaces the peripheral lamin B of the nuclear lamina, we suggest a mechanistic model of nuclear membrane deformation via progerin clustering.