How intracellular organelles acquire their characteristic sizes is a fundamental cell biological question. Given the stereotypical changes in nuclear size in cancer, it is particularly important to understand the mechanisms that control nuclear size in human cells. Here we use a high-throughput imaging RNAi screen to identify and mechanistically characterize ELYS, a nucleoporin required for postmitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. We show that ELYS knockdown results in small nuclei, the accumulation of cytoplasmic lamin aggregates, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import. Increasing nuclear import by importin α overexpression rescues nuclear size and lamin B2 import, while inhibiting importin α/β nuclear import decreases nuclear size. Conversely, ELYS overexpression leads to increased nuclear size, enrichment of nuclear lamin B2 staining at the nuclear periphery, and elevated NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. In summary, we identify ELYS and NPC density as novel positive effectors of mammalian nuclear size and propose that nuclear size is controlled by nuclear import capacity.

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity