Nuclear protein import is reduced in cells expressing nuclear envelopathy-causing lamin A mutants.
Lamins, which form the nuclear lamina, not only constitute an important determinant of nuclear architecture, but additionally play essential roles in many nuclear functions. Mutations in A-type lamins cause a wide range of human genetic disorders (laminopathies). The importance of lamin A (LaA) in the spatial arrangement of nuclear pore complexes (NPCs) prompted us to study the role of LaA mutants in nuclear protein transport. Two mutants, causing prenatal skin disease restrictive dermopathy (RD) and the premature aging disease Hutchinson Gilford progeria syndrome, were used for expression in HeLa cells to investigate their impact on the subcellular localization of NPC-associated proteins and nuclear protein import. Furthermore, dynamics of the LaA mutants within the nuclear lamina were studied. We observed affected localization of NPC-associated proteins, diminished lamina dynamics for both LaA mutants and reduced nuclear import of representative cargo molecules. Intriguingly, both LaA mutants displayed similar effects on nuclear morphology and functions, despite their differences in disease severity. Reduced nuclear protein import was also seen in RD fibroblasts and impaired lamina dynamics for the nucleoporin Nup153. Our data thus represent the first study of a direct link between LaA mutant expression and reduced nuclear protein import.
University of Würzburg, Institute of Anatomy and Cell Biology, Koellikerstrasse 6, 97070 Würzburg, Germany.
Albert
A
Busch
Tilman
T
Kiel
Wolfgang-M
WM
Heupel
Manfred
M
Wehnert
Stefan
S
Hübner
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D034881:Nuclear Lamina / Q000378:metabolism*; D022022:Nuclear Pore / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011371:Progeria / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012871:Skin Diseases / Q000378:metabolism; D000097606:Exportin 1 Protein
D049452:Green Fluorescent Proteins; D028884:Karyopherins; D034904:Lamin Type A; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D000097606:Exportin 1 Protein