Witt Kristen C, Dziulko Adam, An Joohyun, Pekovic Filip, Cheng Arthur Xiuyuan, Liu Grace Y, Lee Ophelia Vosshall, Turner David J, Lari Azra, Gaidt Moritz M, Chavez Roberto, Fattinger Stefan A, Abraham Preethy, Dhaliwal Harmandeep, Lee Angus Y, Kotov Dmitri I, Coscoy Laurent, Glaunsinger Britt A, Valkov Eugene, Chuong Edward B, Vance Russell E
Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
Division of Immunology and Molecular Medicine, University of California, Berkeley, CA, USA.
Nature. 2025 Jun 11. doi: 10.1038/s41586-025-09152-2.
Type I interferons are essential for antiviral immunity but must be tightly regulated. The conserved transcriptional repressor SP140 inhibits interferon-β (Ifnb1) expression through an unknown mechanism. Here we report that SP140 does not directly repress Ifnb1 transcription. Instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of a previously uncharacterized regulator that we call RESIST (regulated stimulator of interferon via stabilization of transcript; previously annotated as annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within punctate structures called nuclear bodies that have important roles in silencing DNA-virus gene expression in the nucleus. Consistent with this observation, we find that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 is independent of its ability to regulate Ifnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity.
I型干扰素对于抗病毒免疫至关重要，但必须受到严格调控。保守的转录抑制因子SP140通过未知机制抑制干扰素-β（Ifnb1）的表达。在此我们报告，SP140并不直接抑制Ifnb1的转录。相反，SP140通过直接抑制一种此前未被鉴定的调节因子（我们称之为RESIST，即通过转录本稳定调节干扰素的刺激因子；以前注释为膜联蛋白2受体）的表达，来负向调节Ifnb1的mRNA稳定性。RESIST通过对抗由RNA结合蛋白三联四肽重复蛋白（TTP）家族和CCR4-NOT去腺苷酸化酶复合体介导的Ifnb1 mRNA去稳定化，来促进Ifnb1 mRNA的稳定性。SP140定位于称为核体的点状结构内，核体在沉默细胞核内的DNA病毒基因表达中起重要作用。与这一观察结果一致，我们发现SP140抑制γ疱疹病毒MHV68的复制。SP140的抗病毒活性与其调节Ifnb1的能力无关。我们的结果确立了SP140的双重抗病毒和干扰素调节功能。我们提出，SP140和RESIST参与抗病毒效应器触发的免疫反应。
