SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity

IF 56.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Pub Date : 2025-06-11 DOI:10.1038/s41586-025-09152-2

Kristen C. Witt, Adam Dziulko, Joohyun An, Filip Pekovic, Arthur Xiuyuan Cheng, Grace Y. Liu, Ophelia Vosshall Lee, David J. Turner, Azra Lari, Moritz M. Gaidt, Roberto Chavez, Stefan A. Fattinger, Preethy Abraham, Harmandeep Dhaliwal, Angus Y. Lee, Dmitri I. Kotov, Laurent Coscoy, Britt A. Glaunsinger, Eugene Valkov, Edward B. Chuong, Russell E. Vance

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引用次数: 0

Abstract

Type I interferons are essential for antiviral immunity1 but must be tightly regulated2. The conserved transcriptional repressor SP140 inhibits interferon-β (Ifnb1) expression through an unknown mechanism3,4. 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 nucleus3. 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 immunity5,6. The antiviral protein SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of the immune regulator RESIST.

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SP140-RESIST通路调节干扰素mRNA稳定性和抗病毒免疫

I型干扰素对抗病毒免疫至关重要，但必须严格调控。保守的转录抑制因子SP140通过未知的机制抑制干扰素-β (Ifnb1)的表达。这里我们报道SP140不直接抑制Ifnb1的转录。相反，SP140通过直接抑制先前未表征的调节因子的表达来负性调节Ifnb1 mRNA的稳定性，我们称之为RESIST(通过转录稳定调节干扰素刺激因子；先前注释为膜联蛋白2受体)。RESIST通过对抗由rna结合蛋白三四丙氨酸（TTP）家族和CCR4-NOT deadenylase复合物介导的Ifnb1 mRNA失稳，促进Ifnb1 mRNA的稳定性。SP140定位于称为核体的点状结构中，核体在沉默细胞核中dna -病毒基因表达中起重要作用3。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的抗病毒活性独立于其调节Ifnb1的能力。我们的研究结果确定了SP140的双重抗病毒和干扰素调节功能。我们认为SP140和RESIST参与了抗病毒效应触发免疫5,6。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature 综合性期刊-综合性期刊

CiteScore

90.00

自引率

1.20%

发文量

3652

审稿时长

3 months

期刊介绍： Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.