Lamins are structural components of the nuclear lamina and integral parts of the nucleoplasm. The tripartite domain structure partitions the molecule into an amino-terminal head, central rod and a carboxy-terminal tail domain. The tail domain contains a nuclear localization sequence and in most
lamins an additional CaaX motif, which is necessary to post-translationally process prelamin to mature
lamin. As players of nuclear and cellular integrity,
lamins must possess unrestrained access to the nucleus. To study whether nuclear trafficking of
lamins is compromised in
laminopathies, we determined relative nuclear import activities between expressed
prelamin A and selected
laminopathy-inducing mutants thereof. Furthermore, the impact of inhibition of maturation on nuclear import of expressed
prelamin A was examined. To perform quantitative transport measurements, import competent but lamina incorporation-deficient GFP- or
DsRed-tagged
prelamin A deletion mutants were used, which lacked the head and rod domain (ΔHR-
prelamin A). Nuclear accumulation of ΔHR-
prelamin A carrying the
lipodystrophy and
metabolic syndrome-inducing mutations R419C and L421P or
progeria-causing deletions was significantly reduced, but that of the maturation-deficient mutant ΔHR-
prelamin A SSIM was significantly increased. In the case of the full length
prelamin A mutants R419C and L421P altered subcellular localization and reduced lamina incorporation were detected, with the
prelamin A-
binding protein Narf being redistributed into R419-containing aggregates. The results suggest that impaired nuclear transport of certain
prelamin A mutants may represent a contributing factor in the pathogenesis of certain
laminopathies.