Progerin, the protein that causes Hutchinson–Gilford progeria syndrome, triggers nuclear membrane (NM) ruptures and blebs, but the mechanisms are unclear. We suspected that the expression of progerin changes the overall structure of the nuclear lamina. High-resolution microscopy of smooth muscle cells (SMCs) revealed that lamin A and lamin B1 form independent meshworks with uniformly spaced openings (~0.085 µm 2 ). The expression of progerin in SMCs resulted in the formation of an irregular meshwork with clusters of large openings (up to 1.4 µm 2 ). The expression of progerin acted in a dominant-negative fashion to disrupt the morphology of the endogenous lamin B1 meshwork, triggering irregularities and large openings that closely resembled the irregularities and openings in the progerin meshwork. These abnormal meshworks were strongly associated with NM ruptures and blebs. Of note, the progerin meshwork was markedly abnormal in nuclear blebs that were deficient in lamin B1 (~50% of all blebs). That observation suggested that higher levels of lamin B1 expression might normalize the progerin meshwork and prevent NM ruptures and blebs. Indeed, increased lamin B1 expression reversed the morphological abnormalities in the progerin meshwork and markedly reduced the frequency of NM ruptures and blebs. Thus, progerin expression disrupts the overall structure of the nuclear lamina, but that effect—along with NM ruptures and blebs—can be abrogated by increased lamin B1 expression.

中文翻译：

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早老蛋白形成异常的网络并对核层具有显性负效应


早衰素是一种导致哈钦森-吉尔福德早衰综合症的蛋白质，可引发核膜 (NM) 破裂和气泡，但其机制尚不清楚。我们怀疑早老蛋白的表达改变了核层的整体结构。平滑肌细胞 (SMC) 的高分辨率显微镜显示，核纤层蛋白 A 和核纤层蛋白 B1 形成独立的网状结构，具有均匀间隔的开口（~0.085 µm） 2 ）。早老素在 SMC 中的表达导致形成不规则的网状结构，具有大开口簇（高达 1.4 µm） 2 ）。早老素的表达以显性失活的方式破坏内源性核纤层蛋白B1网状结构的形态，引发与早老素网状结构中的不规则性和开口非常相似的不规则性和大开口。这些异常的网状结构与 NM 破裂和气泡密切相关。值得注意的是，缺乏核纤层蛋白 B1 的核泡（约占所有泡的 50%）的早老蛋白网络明显异常。该观察结果表明，较高水平的核纤层蛋白 B1 表达可能会使早老蛋白网络正常化，并防止 NM 破裂和气泡。事实上，核纤层蛋白 B1 表达的增加逆转了早老蛋白网络的形态异常，并显着降低了 NM 破裂和气泡的频率。因此，早老蛋白的表达会破坏核纤层的整体结构，但这种影响以及 NM 破裂和气泡可以通过增加核纤层蛋白 B1 的表达来消除。