Cell type-dependent proapoptotic role of Bcl2L12 revealed by a mutation concomitant with the disruption of the juxtaposed Irf3 gene
Cell type-dependent proapoptotic role of Bcl2L12 revealed by a mutation concomitant with the disruption of the juxtaposed Irf3 gene
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DOI：
10.1073/pnas.0905702106
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发表时间：
2009-07-28
影响因子：
11.1
通讯作者：
Tamura, Tomohiko
中科院分区：
文献类型：
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作者：
Nakajima, Akira;Nishimura, Keishiro;Tamura, Tomohiko
缺乏IRF3转录因子表达的小鼠（IRF3（-/-）小鼠）的产生揭示了其在I型IFN应答激活中的关键作用。Bcl2l12基因编码Bcl2l12蛋白，结构上与Bcl-2家族相关，与Irf3基因几乎重叠，先前导入Irf3等位基因的零突变导致Bcl2l12基因功能失活；因此，这些小鼠被正确地称为Irf3(-/-) Bcl2l12（-/-）小鼠。来自Irf3(-/-)Bcl2l12（-/-）小鼠的胚胎成纤维细胞(Irf3（-/-)Bcl2l12(-/-) MEFs）显示出对DNA损伤诱导的凋亡的抗性，并伴有caspase切割受损。这种凋亡缺陷在Irf3(-/-) Bcl2l12(-/-) MEFs中被Bcl2l12的异位表达所挽救，而Irf3却没有。bcl2l12介导的凋亡反应依赖于细胞类型和细胞外刺激。相比之下，先前报道的Irf3(-/-)Bcl2l12(-/-) mef中核酸诱导I型IFN基因的缺陷通过表达Irf3而不是Bcl2l12来修复。因此，本研究一方面揭示了Bcl2L12具有细胞类型依赖性的促凋亡功能，另一方面证实了IRF3在I型IFN应答中的重要作用。
The generation of mice lacking the expression of the IRF3 transcription factor (Irf3(-/-) mice) has revealed its crucial role in the activation of the type I IFN response. The Bcl2l12 gene, encoding Bcl2L12 protein structurally related to the Bcl-2 family, was found to almost overlap with the Irf3 gene, and the null mutation previously introduced into the Irf3 allele resulted in the functional inactivation of the Bcl2l12 gene; therefore, the mice are correctly termed Irf3(-/-) Bcl2l12(-/-) mice. Embryonic fibroblasts from Irf3(-/-)Bcl2l12(-/-) mice (Irf3(-/-)Bcl2l12(-/-) MEFs) showed resistance to DNA damage-induced apoptosis, accompanied by impaired caspase cleavage. This apoptotic defect in Irf3(-/-) Bcl2l12(-/-) MEFs was rescued by the ectopic expression of Bcl2L12, but not IRF3. The Bcl2L12-mediated apoptotic response depended on the cell type and extracellular stimulus. In contrast, the previously reported defect in the induction of type I IFN genes by nucleic acids in Irf3(-/-)Bcl2l12(-/-) MEFs was rescued by expressing IRF3, but not Bcl2L12. Thus, our present study revealed, on the one hand, a cell type-dependent proapoptotic function of Bcl2L12 and, on the other hand, confirmed the essential role of IRF3 in type I IFN response.