Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America.
PLoS One. 2011 Apr 14;6(4):e18842. doi: 10.1371/journal.pone.0018842.
Innate immune signaling is crucial for detection of and the initial response to microbial pathogens. Evidence is provided indicating that LGP2, a DEXH box domain protein related to the RNA recognition receptors RIG-I and MDA5, participates in the cellular response to cytosolic double-stranded DNA (dsDNA). Analysis of embryonic fibroblasts and macrophages from mice harboring targeted disruption in the LGP2 gene reveals that LGP2 can act as a positive regulator of type I IFN and anti-microbial gene expression in response to transfected dsDNA. Results indicate that infection of LGP2-deficient mice with an intracellular bacterial pathogen, Listeria monocytogenes, leads to reduced levels of type I IFN and IL12, and allows increased bacterial growth in infected animals, resulting in greater colonization of both spleen and liver. Responses to infection with vaccinia virus, a dsDNA virus, are also suppressed in cells lacking LGP2, reinforcing the ability of LGP2 to act as a positive regulator of antiviral signaling. In vitro mechanistic studies indicate that purified LGP2 protein does not bind DNA but instead mediates these responses indirectly. Data suggest that LGP2 may be acting downstream of the intracellular RNA polymerase III pathway to activate anti-microbial signaling. Together, these findings demonstrate a regulatory role for LGP2 in the response to cytosolic DNA, an intracellular bacterial pathogen, and a DNA virus, and provide a plausible mechanistic hypothesis as the basis for this activity.
先天免疫信号对于检测和初始应对微生物病原体至关重要。有证据表明，LGP2 是一种与 RNA 识别受体 RIG-I 和 MDA5 相关的 DEXH 盒结构域蛋白，参与细胞对胞质双链 DNA（dsDNA）的反应。对携带 LGP2 基因靶向缺失的小鼠胚胎成纤维细胞和巨噬细胞进行分析表明，LGP2 可以作为转染 dsDNA 时 I 型 IFN 和抗微生物基因表达的正向调节剂。结果表明，缺失 LGP2 的小鼠感染细胞内细菌病原体李斯特菌单核细胞增生李斯特菌后，I 型 IFN 和 IL12 水平降低，感染动物中的细菌生长增加，导致脾脏和肝脏的定植增加。缺乏 LGP2 的细胞对痘苗病毒（一种 dsDNA 病毒）的感染反应也受到抑制，这进一步证实了 LGP2 作为抗病毒信号正向调节剂的能力。体外机制研究表明，纯化的 LGP2 蛋白不与 DNA 结合，而是间接介导这些反应。数据表明，LGP2 可能在细胞内 RNA 聚合酶 III 途径下游发挥作用，激活抗微生物信号。总之，这些发现表明 LGP2 在对胞质 DNA、细胞内细菌病原体和 DNA 病毒的反应中发挥调节作用，并为这种活性提供了一个合理的机制假设。
