title: The defective nuclear lamina in Hutchinson-gilford progeria syndrome disrupts the nucleocytoplasmic Ran gradient and inhibits nuclear localization of Ubc9.
abstract: The mutant form of lamin A responsible for the premature aging disease Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that changes the structure of the nuclear lamina. How the perturbation of the nuclear lamina in progeria is transduced into cellular changes is undefined. Using patient fibroblasts and a variety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndrome inhibits the nucleocytoplasmic transport of several factors with key roles in nuclear function. We found that progerin reduces the nuclear/cytoplasmic concentration of the Ran GTPase and inhibits the nuclear localization of Ubc9, the sole E2 for SUMOylation, and of TPR, the nucleoporin that forms the basket on the nuclear side of the nuclear pore complex. Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and TPR import, indicating that these pathways are linked. Reducing nuclear SUMOylation decreases the nuclear mobility of the Ran nucleotide exchange factor RCC1 in vivo, and the addition of SUMO E1 and E2 promotes the dissociation of RCC1 and Ran from chromatin in vitro. Our data suggest that the cellular effects of progerin are transduced, at least in part, through reduced function of the Ran GTPase and SUMOylation pathways.
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Kelley
authors.forename: Sutirtha
authors.initials: S
authors.lastname: Datta
authors.forename: Chelsi J
authors.initials: CJ
authors.lastname: Snow
authors.forename: Mandovi
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Li
authors.initials: L
authors.lastname: Ni
authors.forename: Adam
authors.initials: A
authors.lastname: Spencer
authors.forename: Chun-Song
authors.initials: CS
authors.lastname: Yang
authors.forename: Caelin
authors.initials: C
authors.lastname: Cubeñas-Potts
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Matunis
authors.forename: Bryce M
authors.initials: BM
authors.lastname: Paschal
mesh_terms: D021581:Active Transport, Cell Nucleus; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D034881:Nuclear Lamina / Q000473:pathology*; D009687:Nuclear Proteins; D011371:Progeria / Q000378:metabolism / Q000473:pathology*; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C120587:RAN protein, human; C062521:RCC1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D020931:ran GTP-Binding Protein; D000098843:Ubiquitin-Conjugating Enzyme UBC9