The role of lamin B receptor in the regulation of senescence-associated secretory phenotype (SASP)
The role of lamin B receptor in the regulation of senescence-associated secretory phenotype (SASP)
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DOI：
10.1016/j.yexcr.2020.111927
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发表时间：
2020-05-01
影响因子：
3.7
通讯作者：
Fujii, Michihiko
中科院分区：
文献类型：
--
作者：
En, Atsuki;Takauji, Yuki;Fujii, Michihiko
细胞衰老是哺乳动物体细胞不可逆的生长停滞现象。衰老细胞增加分泌蛋白如炎性细胞因子的产生，这种现象称为衰老相关分泌表型（SASP）。已知SASP对生物体健康和衰老具有深远的影响;然而，SASP的分子机制尚未确切了解。在我们以前的研究中，我们已经表明，衰老细胞显示核纤层蛋白B受体（LBR），一种调节异染色质组织的核膜蛋白的功能下降。在这里，我们研究了LBR在SASP调控中的意义，因为衰老细胞显示出改变的异染色质组织，这将影响基因表达。我们发现，敲低LBR上调HeLa细胞中SASP因子如IL-6、IL-8和MMP 1的表达，即使LBR敲低并不诱导细胞衰老。相反，LBR的强制表达抑制了它们在过量胸苷诱导的衰老细胞中的上调表达。此外，我们的基因表达谱分析也表明，许多分泌蛋白的上调LBR敲低。我们分析了LBR对SASP因子表达的调控机制，发现这些SASP因子的启动子在正常生长的细胞中与LBR相关，而在衰老细胞中与LBR分离。此外，我们发现LBR的强制表达减少了衰老细胞中可能参与SASP的细胞质DNA的产生。这些结果表明，LBR在SASP的调节中起着至关重要的作用。
Cellular senescence is a phenomenon of irreversible growth arrest of mammalian somatic cells. Senescent cells increase the production of secretory proteins such as inflammatory cytokines, a phenomenon termed senescenceassociated secretory phenotype (SASP). SASP is known to have profound effects on organismal health and aging; however, the molecular mechanisms of SASP are not precisely understood. In our previous studies, we have shown that senescent cells show decreased function of lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization. Here we examined the implication of LBR in the regulation of SASP because senescent cells show altered heterochromatin organization, which would affect gene expression. We found that knock-down of LBR up-regulated the expression of the SASP factors such as IL-6, IL-8, and MMP1 in HeLa cells, even though cellular senescence was not induced by LBR knock-down. Conversely, enforced expression of LBR suppressed their up-regulated expression in senescent cells induced by excess thymidine. Further, our gene expression profile analysis also showed that many secretory proteins were up-regulated by LBR knock-down. We then analyzed the regulatory mechanisms of the expression of SASP factors by LBR, and found that the promoters of these SASP factors associated with LBR in normally growing cells, but dissociated from it in senescent cells. Additionally, we found that enforced expression of LBR decreased the generation of cytoplasmic DNA, which could be involved in SASP, in senescent cells. These findings suggested that LBR would play crucial roles in the regulation of SASP.