title: Nuclear localization signal deletion mutants of lamin A and progerin reveal insights into lamin A processing and emerin targeting.
abstract: Lamin A is a major component of the lamina, which creates a dynamic network underneath the nuclear envelope. Mutations in the lamin A gene (LMNA) cause severe genetic disorders, one of which is Hutchinson-Gilford progeria syndrome (HGPS), a disease triggered by a dominant mutant named progerin. Unlike the wild-type lamin A, whose farnesylated C-terminus is excised during post-translational processing, progerin retains its farnesyl tail and accumulates on the nuclear membrane, resulting in abnormal nuclear morphology during interphase. In addition, membrane-associated progerin forms visible cytoplasmic aggregates in mitosis. To examine the potential effects of cytoplasmic progerin, nuclear localization signal (NLS) deleted progerin and lamin A (PGΔNLS and LAΔNLS, respectively) have been constructed. We find that both ΔNLS mutants are farnesylated in the cytosol and associate with a sub-domain of the ER via their farnesyl tails. While the farnesylation on LAΔNLS can be gradually removed, which leads to its subsequent release from the ER into the cytoplasm, PGΔNLS remains permanently farnesylated and membrane-bounded. Moreover, both ΔNLS mutants dominantly affect emerin's nuclear localization. These results reveal new insights into lamin A biogenesis and lamin A-emerin interaction.
authors.affiliation: Department of Cell Biology and Molecular Genetics; University of Maryland; College Park, MD USA.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Cell Biology and Molecular Genetics; University of Maryland; College Park, MD USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Flannery
authors.affiliation: Department of Cell Biology and Molecular Genetics; University of Maryland; College Park, MD USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Cell Biology and Molecular Genetics; University of Maryland; College Park, MD USA.
authors.forename: Eunae
authors.initials: E
authors.lastname: Ko
authors.affiliation: Department of Cell Biology and Molecular Genetics; University of Maryland; College Park, MD USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Cao
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D009154:Mutation; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011371:Progeria / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D034904:Lamin Type A; D008565:Membrane Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D011498:Protein Precursors; C092710:emerin; C090764:prelamin A; D051231:Farnesyltranstransferase
keywords: ZMPSTE24; emerin; farnesylation; lamin; nuclear localization signal; progeria