Progerin-induced nuclear envelope remodeling is shaped by cell division and NUP153.

The nuclear envelope (NE) undergoes dynamic remodeling during both physiological and pathological processes. Nuclei in cells from people with accelerated aging diseases and from older individuals are often lobular and convoluted. Despite extensive study, the steps of phenotype acquisition and the co-factors required are not yet fully understood. Here, we focused on progerin, a variant form of lamin A that causes Hutchinson-Gilford progeria syndrome (HGPS). Using an inducible cell-based system, we characterized two distinct stages of NE remodeling. Correlative light and electron microscopy of interphase-arrested cells showed that prior to cell division, progerin primarily affects the inner nuclear membrane (INM), inducing focal expansion, invagination and the formation of multi-membranous structures, whereas the outer nuclear membrane remains largely unaffected. These focal regions of progerin accumulation are enriched for specific INM proteins and the nucleoporin NUP153 but largely exclude nuclear pore complexes. Live and fixed image analysis demonstrated that, upon cell division and NE reassembly, progerin-expressing cells develop pronounced nuclear lobulations characteristic of HGPS. Appreciation of this stepwise development of phenotype lends insight into cellular manifestations of aging in mitotic versus post-mitotic cell types and provides a system in which to study factors that contribute to these distinct stages in the disruption of nuclear morphology. Depletion of NUP153 reduced NE foci formation in interphase-arrested cells expressing GFP-progerin, suggesting that NUP153 promotes or stabilizes INM invagination. Aberrant nuclear architecture is just one cellular feature that changes during normal and accelerated aging, but its etiology provides a crucial framework for understanding accompanying consequences on chromatin packaging, DNA damage and the endoplasmic reticulum stress response.