The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling.
The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling.
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DOI：
10.1371/journal.pone.0070994
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hawiger J
中科院分区：
文献类型：
--
作者：
Sethman CR;Hawiger J
不育蛋白SARM是Toll样受体接头MyD88家族中高度保守且结构独特的成员，在先天免疫信号转导和细胞凋亡中发挥重要作用。其细胞内作用的确切机制尚不清楚。细胞凋亡是一种古老而普遍的细胞程序性死亡过程，它会导致核层的破坏，最终导致细胞核的解体。除了支持核膜外，层蛋白还在染色质组织、表观遗传调控、转录、核运输和有丝分裂中发挥重要作用。导致核层不稳定的突变和其他损害(椎板病)是许多人类顽固性疾病的基础。在这里，我们报道了SARM通过其氨基末端Armadillo重复区域移位到人胚胎肾细胞的核。在细胞核内，SARM形成了一种以前未见报道的晶格，类似于核层支架。此外，我们还表明，SARM保护Lamins免受细胞凋亡降解，并减少核小体间DNA片段化，以响应促炎症细胞因子肿瘤坏死因子α诱导的信号。这些发现表明，在炎症驱动的人类细胞凋亡过程中，天然免疫适配器SARM与核层稳定之间存在重要联系。
Sterile alpha and armadillo-motif containing protein (SARM), a highly conserved and structurally unique member of the MyD88 family of Toll-like receptor adaptors, plays an important role in innate immunity signaling and apoptosis. Its exact mechanism of intracellular action remains unclear. Apoptosis is an ancient and ubiquitous process of programmed cell death that results in disruption of the nuclear lamina and, ultimately, dismantling of the nucleus. In addition to supporting the nuclear membrane, lamins serve important roles in chromatin organization, epigenetic regulation, transcription, nuclear transport, and mitosis. Mutations and other damage that destabilize nuclear lamins (laminopathies) underlie a number of intractable human diseases. Here, we report that SARM translocates to the nucleus of human embryonic kidney cells by using its amino-terminal Armadillo repeat region. Within the nucleus, SARM forms a previously unreported lattice akin to the nuclear lamina scaffold. Moreover, we show that SARM protects lamins from apoptotic degradation and reduces internucleosomal DNA fragmentation in response to signaling induced by the proinflammatory cytokine Tumor Necrosis Factor alpha. These findings indicate an important link between the innate immunity adaptor SARM and stabilization of nuclear lamins during inflammation-driven apoptosis in human cells.
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