Department of Biology, Drew University, 36 Madison Avenue, Madison, NJ 07940, United States.
Department of Biology, Drew University, 36 Madison Avenue, Madison, NJ 07940, United States.
Mol Immunol. 2018 Jul;99:182-190. doi: 10.1016/j.molimm.2018.05.014. Epub 2018 May 26.
Recent studies have highlighted the importance of immune sensing of cytosolic DNA of both pathogen and host origin. We aimed to examine the role of DNA sensors interferon-γ-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) in responding to cytosolic DNA. We show IFI16 and cGAS can synergistically induce IFNb transcriptional activity in response to cytoplasmic DNA. We also examined the role of polyglutamine binding protein 1 (PQBP1), a protein predominantly expressed in lymphoid and myeloid cells that has been shown to lead to type I interferon production in response to retroviral infection. We show PQBP1 associates with cGAS and IFI16 in THP-1 cells. Unexpectedly, knockout of PQBP1 in THP-1 cells causes significantly increased type I IFN production in response to transfected cytosolic nucleic acids or DNA damage, unlike what is seen in response to retroviral infection. Overexpression of PQBP1 in HEK293 T cells impairs IFI16/cGAS-induced IFNb transcriptional activity. In human cancer patients, low expression of PQBP1 is correlated with improved survival, the opposite correlation of that seen with cGAS or IFI16 expression. Our findings suggest that PQBP1 inhibits IFI16/cGAS-induced signaling in response to cytosolic DNA, in contrast to the role of this protein in response to retroviral infection.
最近的研究强调了先天免疫识别胞质 DNA 的重要性，无论是病原体还是宿主来源的 DNA。我们旨在研究 DNA 传感器干扰素-γ诱导蛋白 16（IFI16）和环鸟苷酸-腺苷酸合酶（cGAS）在应对胞质 DNA 时的作用。结果表明，IFI16 和 cGAS 可以协同诱导 IFNb 转录活性以响应细胞质 DNA。我们还研究了多聚谷氨酰胺结合蛋白 1（PQBP1）的作用，该蛋白主要在淋巴样和髓样细胞中表达，已被证明可在逆转录病毒感染时导致 I 型干扰素的产生。我们表明 PQBP1 在 THP-1 细胞中与 cGAS 和 IFI16 相关。出乎意料的是，与逆转录病毒感染不同，在 THP-1 细胞中敲除 PQBP1 会导致转染的胞质核酸或 DNA 损伤时显著增加 I 型 IFN 的产生。在 HEK293T 细胞中过表达 PQBP1 会损害 IFI16/cGAS 诱导的 IFNb 转录活性。在人类癌症患者中，PQBP1 的低表达与改善的存活率相关，这与 cGAS 或 IFI16 表达的相关性相反。我们的研究结果表明，与逆转录病毒感染相反，PQBP1 抑制 IFI16/cGAS 诱导的胞质 DNA 信号通路。
