美国加州大学Russell E. Vance团队在研究中取得进展。他们研制了SP140-RESIST通路调节干扰素mRNA稳定性和抗病毒免疫。这一研究成果于2025年6月11日发表在国际顶尖学术期刊《自然》上。

这里课题组研究人员报道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，研究组称之为RESIST(通过转录稳定调节干扰素刺激因子；以前被注释为膜联蛋白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定位于被称为核小体的点状结构中，在沉默核小体中DNA-病毒基因表达方面起着重要作用。与这一观察结果一致，研究团队发现SP140抑制了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。他们的研究结果确定了SP140的双重抗病毒和干扰素调节功能。研究团队认为SP140和RESIST参与了抗病毒效应触发免疫。

研究人员表示，I型干扰素对抗病毒免疫至关重要，但它们受到严格调控。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。

附：英文原文

Title: SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity

Author: 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.

Issue&Volume: 2025-06-11

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.

DOI: 10.1038/s41586-025-09152-2

Source: https://www.nature.com/articles/s41586-025-09152-2