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Inhibiting Farnesylation of Progerin Prevents the Characteristic Nuclear Blebbing of Hutchinson–Gilford Progeria Syndrome

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Inhibiting Farnesylation of Progerin Prevents the Characteristic Nuclear Blebbing of Hutchinson–Gilford Progeria Syndrome Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson–Gilford progeria syndrome Brian C. Capell*†, Michael R. Erdos*, James P. Madigan‡§¶, James J. Fiordalisi‡§, Renee Varga*, Karen N. Conneelyʈ, Leslie B. Gordon*, Channing J. Der‡¶**, Adrienne D. Cox‡§¶**, and Francis S. Collins*†† *Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, MSC 8004, Bethesda, MD 20892-8004; †Howard Hughes Medical Institute–National Institutes of Health Research Scholars Program, 1 Cloister Court, Building 60, Bethesda, MD 20814-1460; ‡Lineberger Comprehensive Cancer Center, Departments of §Radiation Oncology and **Pharmacology, and ¶Curriculum in Genetics and Molecular Biology, University of North Carolina, 101 Manning Drive, Chapel Hill, NC 27599; and ʈDepartment of Biostatistics, University of Michigan School of Public Health, 1420 Washington Heights, Ann Arbor, MI 48109 Contributed by Francis S. Collins, July 18, 2005 Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic clear shape, and cell division (7). In the LMNA gene, Ͼ180 disorder that is characterized by dramatic premature aging and mutations have been reported, and currently, there are eight accelerated cardiovascular disease. HGPS is almost always caused diseases in addition to HGPS (referred to as the ‘‘laminopa- by a de novo point mutation in the lamin A gene (LMNA) that thies’’) that are associated with various mutations in this gene activates a cryptic splice donor site, producing a truncated mutant (7). These diseases include disorders such as Emery–Dreifuss protein termed ‘‘progerin.’’ WT prelamin A is anchored to the muscular dystrophy, mandibuloacral dysplasia, atypical Werner’s nuclear envelope by a farnesyl isoprenoid lipid. Cleavage of the syndrome, dilated cardiomyopathy type 1A, restrictive dermop- terminal 15 aa and the farnesyl group releases mature lamin A from athy, and Dunnigan-type familial partial lipodystrophy (8, 9). this tether. In contrast, this cleavage site is deleted in progerin. We The typical LMNA mutation in HGPS is a C-to-T nucleotide hypothesized that retention of the farnesyl group causes progerin substitution at position 1824 causing no change in the encoded to become permanently anchored in the nuclear membrane, dis- amino acid (G608G) but creating a cryptic splice donor site. rupting proper nuclear scaffolding and causing the characteristic Activation of this site results in an mRNA lacking 150 nucleo- nuclear blebbing seen in HGPS cells. Also, we hypothesized that tides. In turn, this mRNA is translated into a mutant protein, blocking farnesylation would decrease progerin toxicity. To test termed ‘‘progerin’’ (4), with a 50-aa internal deletion near the C this hypothesis, the terminal CSIM sequence in progerin was terminus. LA is normally expressed by most differentiated cells, mutated to SSIM, a sequence that cannot be farnesylated. SSIM where it integrally affects both nuclear membrane structure and progerin relocalized from the nuclear periphery into nucleoplasmic function (10). Progerin apparently acts in a dominant-negative aggregates and produced no nuclear blebbing. Also, blocking manner on the nuclear function of cell types that express LA (11, farnesylation of authentic progerin in transiently transfected HeLa, 12). In addition to the potential mechanical fragility that is HEK 293, and NIH 3T3 cells with farnesyltransferase inhibitors (FTIs) created by disrupting the nuclear lamina, this mutation also may restored normal nuclear architecture. Last, treatment of both early- affect other vital cellular processes such as gene transcription, and late-passage human HGPS fibroblasts with FTIs resulted in DNA replication, and cell division. significant reductions in nuclear blebbing. Our results suggest that In normal cells, the prelamin A protein contains a CAAX treatment with FTIs represents a potential therapy for patients tetrapeptide motif at the C terminus. This tetrapeptide signals with HGPS. the addition of a 15-carbon farnesyl isoprenoid lipid group to the cysteine by the enzyme farnesyltransferase (FTase) (13). The aging ͉ lamin ͉ laminopathy CAAX motif is a cysteine followed by two aliphatic amino acids and a terminal ‘‘X’’ residue. This final amino acid defines the utchinson–Gilford progeria syndrome (HGPS) is an ex- specificity for the addition of an isoprenyl group with methio- Htremely rare and uniformly fatal ‘‘premature aging’’ disease nine, serine, glutamine, or alanine signaling modification by in which all children die as a consequence of myocardial infarc- FTase and with leucine signaling the addition of a 20-carbon tion or cerebrovascular accident at an average age of 12 years geranylgeranyl isoprenoid group catalyzed by the structurally (range, 8–21 years). The earliest manifestations of the disease related enzyme geranylgeranyltransferase (GGTase) I (14). For are seen at Ϸ12–14 months of age and include alopecia and LA, the CAAX motif is CSIM. Farnesylation, together with growth retardation (Progeria Research Foundation’s medical subsequent CAAX-signaled modifications, promote prelamin A and research database). In addition to progressive atheroscle- association with the nuclear membrane (15). After farnesylation, rosis, HGPS is characterized by bone deformations, including the terminal three AAX amino acids are removed, and the craniofacial disproportion, mandibular and clavicular hypopla- C-terminal cysteine undergoes methyl esterification (16, 17). sia, and osteoporosis, as well as by a loss of s.c. fat, delayed Although both B-type lamins and LA are farnesylated and dentition, sclerodermatous skin, joint stiffness, and hip disloca- carboxymethylated, unique to LA is a second cleavage inside the tions (1–3). nucleus causing the removal of an additional 15 C-terminal HGPS is a sporadic autosomal dominant disease caused in amino acids from the mature protein, including the farnesylated MEDICAL SCIENCES nearly all cases by a de novo single-base substitution in codon 608 of exon 11 of the LMNA gene on chromosome 1 (4, 5). The LMNA gene encodes three proteins, lamin A (LA), LC, and Abbreviations: HGPS, Hutchinson–Gilford progeria syndrome; LA͞C, lamin A͞C; FTase, ⌬ farnesyltransferase; FTI, FTase inhibitor; GGTase, geranylgeranyltransferase; GGTI, GGTase LA 10, all of which are components of the nuclear lamina, a inhibitor. dynamic molecular interface located inside the inner nuclear ††To whom correspondence should be addressed at: National Human Genome Research membrane (6). Initially believed to be an inert scaffolding Institute, National Institutes of Health, Building 31, Room 4B09, 31 Center Drive, MSC network, the lamina has now been shown to have significant roles 2152, Bethesda, MD 20892-2152. E-mail: [email protected]. in DNA replication, transcription, chromatin organization, nu- © 2005 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0506001102 PNAS ͉ September 6, 2005 ͉ vol. 102 ͉ no. 36 ͉ 12879–12884 Downloaded by guest on September 27, 2021 mutations were created by site-directed mutagenesis using the following oligonucleotides: CSIL, 5Ј-CCCCAGAACTGCAG- CATCTTATAATCTAGAGTCGACGGTA-3Ј; and SSIM, 5Ј-CCAGAGCCCCCAGAACTCAAGCATCATGTAATCT- AGAG-3Ј (QuikChange II XL site-directed mutagenesis kit, Stratagene). Cell Culture. The cell lines used were the normal human fibroblast line AG06299 and the HGPS fibroblast lines AG06917, AG11513, and AG11498 (NIA Aging Cell Culture Repository, Coriell Cell Repositories, Camden, NJ). Fibroblasts were cul- tured in MEM (Invitrogen͞GIBCO) supplemented with 15% FBS (HyClone)͞2mML-glutamine͞50 units/ml penicillin͞50 mg/ml streptomycin. HeLa and HEK 293 cell lines were cultured in DMEM (Invitrogen͞GIBCO) supplemented with 10% FBS and antibiotics. Fig. 1. Translation of the LMNA gene yields the prelamin A protein, which requires posttranslational processing for incorporation into the nuclear lam- Transient Transfections. Cells were plated at Ϸ25,000 cells per ina. The prelamin A protein contains a CAAX box at the C terminus that signals chamber of four-chamber slides (Nunc no. 154526, Lab-Tek, isoprenylation (in this case, the addition of a farnesyl group to the cysteine by Nalge). After 24 h, HeLa and HEK 293 cell lines were transiently the enzyme FTase). After farnesylation, the terminal three amino acids (SIM) transfected with 0.8 ␮g of each construct by using Lipofectamine are cleaved, and the terminal farnesylated cysteine undergoes methyl ester- 2000 (Invitrogen) under standard conditions. ification. A second cleavage step by the ZMPSTE24 endoprotease then re- moves the terminal 15 aa, including the farnesyl group. This final cleavage step is blocked in progeria. FTI Treatment. At the time of transient transfection, HeLa cells were treated with one dose of 0, 0.5, 1.0, or 2.0 ␮M selective FTI lonafarnib (Sarasar SCH66336, Schering-Plough). HEK 293 cells cysteine. This final cleavage step and the resulting loss of the were treated with one dose of 0, 1, 2, 5, or 10 ␮M selective FTI farnesyl anchor presumably releases prelamin A from the nu- L-744832 (Biomol, Plymouth Meeting, PA). Also, NIH 3T3 cells clear membrane and allows it to be inserted into the nuclear were treated with 5 ␮M FTI-2153, which is highly selective for lamina. In HGPS, although preprogerin can be farnesylated, its FTase, or GGTase inhibitor (GGTI)-2166, which is highly internal deletion of amino acids 606–656 removes the endopro- selective for GGTase I (kind gifts of S. M.
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