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
复制标题
DOI：
10.1073/pnas.0506001102
复制
发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Collins, FS
中科院分区：
文献类型：
--
作者：
Capell, BC;Erdos, MR;Collins, FS
Hutchinson-Gilford早衰综合征（HIGIRS）是一种罕见的遗传性疾病，其特征是急剧的过早衰老和加速的心血管疾病。HIPPS几乎总是由核纤层蛋白A基因（LMNA）中的从头点突变引起，该点突变激活隐蔽剪接供体位点，产生称为“早老蛋白”的截短突变蛋白。WT前层蛋白A通过法尼基类异戊二烯脂质锚定在核膜上。末端15个氨基酸和法呢基基团的裂解从该系链释放成熟的核纤层蛋白A。相反，早老蛋白中的切割位点被删除。我们假设法呢基基团的保留导致早老蛋白永久锚定在核膜中，破坏适当的核支架并导致HGPS细胞中观察到的特征性核起泡。此外，我们假设阻断法尼基化会降低早老蛋白的毒性。为了检验这一假设，将早老蛋白中的末端CSIM序列突变为SSIM，即不能被法尼基化的序列。SSIM早老蛋白从核周围重新定位到核质聚集体中，并且不产生核起泡。此外，在瞬时转染的HeLa，HEK 293和NIH 3 T3细胞中，用法尼基转移酶抑制剂（FTIs）阻断真正的早老蛋白的法尼基化，恢复了正常的核结构。最后，用FTIs处理早代和晚代人HGPS成纤维细胞导致核起泡显著减少。我们的研究结果表明，FTIs治疗是HGPS患者的一种潜在治疗方法。
Hutchinson-Gilford progeria syndrome (HIGIRS) is a rare genetic disorder that is characterized by dramatic premature aging and accelerated cardiovascular disease. HIGIPS is almost always caused by a de novo point mutation in the lamin A gene (LMNA) that activates a cryptic splice donor site, producing a truncated mutant protein termed "progerin." WT prelamin A is anchored to the nuclear envelope by a farnesyl isoprenoid lipid. Cleavage of the terminal 15 aa and the farnesyl group releases mature lamin A from this tether. In contrast, this cleavage site is deleted in progerin. We hypothesized that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear membrane, disrupting proper nuclear scaffolding and causing the characteristic nuclear blebbing seen in HGPS cells. Also, we hypothesized that blocking farnesylation would decrease progerin toxicity. To test this hypothesis, the terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot be farnesylated. SSIM progerin relocalized from the nuclear periphery into nucleoplasmic aggregates and produced no nuclear blebbing. Also, blocking farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, and NIH 3T3 cells with farnesyltransferase inhibitors (FTIs) restored normal nuclear architecture. Last, treatment of both early- and late-passage human HGPS fibroblasts with FTIs resulted in significant reductions in nuclear blebbing. Our results suggest that treatment with FTIs represents a potential therapy for patients with HGPS.