Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Immunity. 2019 Mar 19;50(3):591-599.e6. doi: 10.1016/j.immuni.2019.02.009.
Immune suppression is a crucial component of immunoregulation and a subgroup of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing proteins (NLRs) attenuate innate immunity. How this inhibitory function is controlled is unknown. A key question is whether microbial ligands can regulate this inhibition. NLRC3 is a negative regulator that attenuates type I interferon (IFN-I) response by sequestering and attenuating stimulator of interferon genes (STING) activation. Here, we report that NLRC3 binds viral DNA and other nucleic acids through its LRR domain. DNA binding to NLRC3 increases its ATPase activity, and ATP-binding by NLRC3 diminishes its interaction with STING, thus licensing an IFN-I response. This work uncovers a mechanism wherein viral nucleic acid binding releases an inhibitory innate receptor from its target.
免疫抑制是免疫调节的一个关键组成部分，核苷酸结合域（NBD）、富含亮氨酸重复序列（LRR）的蛋白质（NLRs）亚群减弱先天免疫。目前尚不清楚如何控制这种抑制功能。一个关键问题是微生物配体是否可以调节这种抑制。NLRC3 是一种负调节剂，通过隔离和减弱干扰素基因刺激物（STING）的激活来减弱 I 型干扰素（IFN-I）反应。在这里，我们报告 NLRC3 通过其 LRR 结构域与病毒 DNA 和其他核酸结合。DNA 与 NLRC3 的结合增加了其 ATP 酶活性，而 NLRC3 的 ATP 结合减少了其与 STING 的相互作用，从而许可 IFN-I 反应。这项工作揭示了一种机制，即病毒核酸结合将抑制性先天受体从其靶标中释放出来。
