Interferon-Inducible Protein 16 (IFI16) Has a Broad-Spectrum Binding Ability Against ssDNA Targets: An Evolutionary Hypothesis for Antiretroviral Checkpoint
Interferon-Inducible Protein 16 (IFI16) Has a Broad-Spectrum Binding Ability Against ssDNA Targets: An Evolutionary Hypothesis for Antiretroviral Checkpoint
复制标题
DOI：
10.3389/fmicb.2019.01426
复制
发表时间：
2019-07-04
影响因子：
5.2
通讯作者：
Magiorkinis, Gkikas
中科院分区：
文献类型：
--
作者：
Hurst, Tara Patricia;Aswad, Amr;Magiorkinis, Gkikas
人内源性逆转录病毒（HERV）受基因组和表观遗传控制，但可在正常组织中表达，产生RNA转录物，其中一些被翻译。虽然在现代人类中还没有实验证明，但HERV RNA（即HERV-K HML-2或HK 2）的cDNA拷贝是在人类-黑猩猩分裂后产生的，直到至少25万年前。我们感兴趣的是确定这样的cDNA是否可以作为先天免疫应答的模式识别受体（PRRs）的配体。针对DNA的AIM-2样受体、干扰素-γ-诱导蛋白16（IFI 16）和环GMP-AMP合酶（cGAS）是候选PRR。IFI 16可以检测HIV-1复制过程中产生的cDNA，导致T细胞死亡增加。虽然HIV-1最近才作为人类病原体出现，但IFI 16的cDNA功能可能是在人类进化过程中选择的。在这里，我们提出了一个新的假设，即已经在人类祖先的基因组中增殖了3000万年的HK 2的逆转录产物可以与IFI 16相互作用。为了支持我们的假设，我们提供了初步数据，显示IFI 16（而不是cGAS）与对应于逆转录的第一产物的合成单链HK 2寡核苷酸相互作用。此外，我们表明，IFI 16的ssDNA检测具有变异性的序列特征，但不依赖于强大的二级结构模仿dsDNA。在HK 2寡核苷酸中，IFI 16与衍生自LTR的那些寡核苷酸的相互作用更强烈，表明这些寡核苷酸具有允许IFI 16以更大亲和力结合的未确定结构特征。此外，发现具有天然允许HK 2表达的干细胞特征的细胞表达先天免疫系统的许多组分，包括cGAS但不表达IFI 16。基于所呈现的初步数据，我们进一步假设另一种假设：人细胞中的IFI 16功能性一直充当控制体细胞组织中异常HK 2复制的“第二线”防御。在干细胞和干细胞系中缺乏这种蛋白质可以允许这些细胞表达HERV，这有助于干细胞的身份。最后，我们还评论了可能支持或反驳我们假设的潜在研究。
Human endogenous retroviruses (HERVs) are under genomic and epigenetic control but can be expressed in normal tissues, producing RNA transcripts some of which are translated. While it has not been demonstrated experimentally in modern humans, cDNA copies from HERV RNA (namely HERV-K HML-2 or HK2) were produced after the human-chimp split and until at least 250,000 years ago. We were interested in determining if such cDNA could be a ligand for pattern recognition receptors (PRRs) of the innate immune response. The AIM-2-like receptors for DNA, interferon-gamma-inducible protein 16 (IFI16) and Cyclic GMP-AMP synthase (cGAS) were candidate PRRs. IFI16 can detect cDNA produced during HIV-1 replication, causing increased T cell death. While HIV-1 has emerged relatively recently as a human pathogen, the cDNA functionality of IFI16 could have been selected for during the course of human evolution. Here we present a novel hypothesis that the products of reverse transcription of HK2, which has been proliferating in the genome of human ancestors for 30 million years, could interact with IFI16. In support of our hypothesis, we provide preliminary data showing that IFI16 (but not cGAS) interacts with synthetic single-stranded HK2 oligos corresponding to the first product of reverse transcription. Further, we show that ssDNA detection by IFI16 has variability with respect to sequence features but is not dependent on strong secondary structures mimicking dsDNA. Among the HK2 oligos, IFI16 interacts more intensely with those derived from LTRs, suggesting these oligos have undetermined structural features that allow IFI16 to bind with greater affinity. Further, cells with stem cell features that naturally allow HK2 expression were found to express many components of the innate immune system including cGAS but not IFI16. Based on the presented preliminary data we further postulate another hypothesis: that the IFI16 functionality in human cells has been acting as "second-line" defense to control abnormal HK2 replication in somatic tissues. The absence of this protein in stem cells and a stern cell line could permit these cells to express HERVs which contribute to stern cell identity. Finally, we also comment on potential studies that could support or refute our hypothesis.