Institut de Génétique Humaine, CNRS, Université de Montpellier, Molecular Basis of Inflammation Laboratory, Montpellier, France.
Azelead, Montpellier, France.
Front Immunol. 2021 Apr 26;12:660560. doi: 10.3389/fimmu.2021.660560. eCollection 2021.
The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.
在多细胞生物中，基因组稳定性的维持依赖于 DNA 损伤反应（DDR）。DDR 包含几个相互关联的途径，它们共同合作以确保基因组损伤的修复。除了它们的修复功能外，几种 DDR 蛋白已被证明参与了炎症反应的发生。特别是，已经报道了 DDR 的几个因子在检测细胞质病理性核酸时引发先天免疫激活。相反，模式识别受体（PRRs）最初被描述为专门用于检测细胞质免疫刺激性核酸，已被发现调节 DDR。因此，尽管最初被描述为在特定的亚细胞定位中起作用，但 DDR 和核酸免疫传感器的因子可能参与相互关联的途径，可能相互影响效率。在这篇迷你综述中，我们讨论了 PRRs 和 DDR 因子之间串扰的证据。为此，我们主要关注环鸟苷酸-腺苷酸（cGAMP）合成酶（cGAS）和干扰素 γ诱导蛋白 16（IFI16），作为涉及检测异常核酸种类的主要 PRRs，以及 DNA 依赖性蛋白激酶（DNA-PK）复合物的成分，该复合物参与双链断裂的修复，最近被描述为潜在的 PRRs。最后，我们讨论了 DDR 和核酸相关干扰素反应之间的串扰如何协同精细调节先天免疫激活，并因此决定病理结果。了解这种合作的分子决定因素对于未来治疗方法的设计至关重要。
