DDIT3 Targets Innate Immunity via the DDIT3-OTUD1-MAVS Pathway To Promote Bovine Viral Diarrhea Virus Replication
DDIT3 Targets Innate Immunity via the DDIT3-OTUD1-MAVS Pathway To Promote Bovine Viral Diarrhea Virus Replication
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DDIT3 通过 DDIT3-OTUD1-MAVS 途径靶向先天免疫，促进牛病毒性腹泻病毒复制
DOI：
10.1128/jvi.02351-20
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发表时间：
2021-03-01
影响因子：
5.4
通讯作者：
He, Hongbin
中科院分区：
文献类型：
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作者：
Wang, Song;Hou, Peili;He, Hongbin
广泛的研究已经证明了DDIT 3在病毒感染期间的细胞凋亡和自噬中的作用。然而，DDIT 3在先天免疫中的作用在很大程度上仍然未知。摘要DNA损伤诱导转录本3（DDIT 3）在内质网应激诱导的细胞凋亡和自噬中起重要作用，但其在天然免疫中的作用尚不清楚。在这里，我们报告说，DDIT 3抑制牛病毒性腹泻病毒（BVDV）感染过程中的抗病毒免疫反应，通过靶向线粒体抗病毒信号（MAVS）在Madin-Darby牛肾（MDBK）细胞和小鼠。BVDV感染可诱导DDIT 3 mRNA和蛋白的高表达。DDIT 3过表达抑制I型干扰素（IFN-I）和IFN刺激的基因产生，从而促进BVDV复制，而DDIT 3敲低促进抗病毒先天免疫应答，抑制病毒复制。DDIT 3促进NF-κ B依赖性卵巢肿瘤（OTU）去泛素化酶1（OTUD 1）表达。此外，OTUD 1通过去泛素化Smurf 1诱导E3泛素连接酶Smurf 1的上调，Smurf 1以泛素化依赖性方式降解MDBK细胞中的MAVS，最终抑制IFN-I的产生。敲除DDIT 3基因可促进抗病毒天然免疫应答，减少BVDV在小鼠体内的复制和病理变化。这些发现为DDIT 3通过调节MAVS降解抑制IFN-I产生的分子机制提供了直接的见解。重要性广泛的研究已经证明了DDIT 3在病毒感染期间的细胞凋亡和自噬中的作用。然而，DDIT 3在先天免疫中的作用在很大程度上仍然未知。在这里，我们表明，DDIT 3是积极调节牛病毒性腹泻病毒（BVDV）感染的Madin-Darby牛肾（MDBK）细胞，并能显着提高BVDV复制。重要的是，DDIT 3通过激活NF-κB信号通路诱导OTU去泛素化酶1（OTUD 1）表达，从而增加细胞内Smurf 1蛋白水平，以降解MAVS并抑制BVDV感染期间IFN-I的产生。总之，这些结果表明DDIT 3在宿主先天免疫抑制和病毒感染促进中发挥关键作用。
Extensive studies have demonstrated roles of DDIT3 in apoptosis and autophagy during viral infection. However, the role of DDIT3 in innate immunity remains largely unknown. ABSTRACT DNA damage-inducible transcript 3 (DDIT3) plays important roles in endoplasmic reticulum (ER) stress-induced apoptosis and autophagy, but its role in innate immunity is not clear. Here, we report that DDIT3 inhibits the antiviral immune response during bovine viral diarrhea virus (BVDV) infection by targeting mitochondrial antiviral signaling (MAVS) in Madin-Darby bovine kidney (MDBK) cells and in mice. BVDV infection induced high DDIT3 mRNA and protein expression. DDIT3 overexpression inhibited type I interferon (IFN-I) and IFN-stimulated gene production, thereby promoting BVDV replication, while DDIT3 knockdown promoted the antiviral innate immune response to suppress viral replication. DDIT3 promoted NF-κB-dependent ovarian tumor (OTU) deubiquitinase 1 (OTUD1) expression. Furthermore, OTUD1 induced upregulation of the E3 ubiquitin ligase Smurf1 by deubiquitinating Smurf1, and Smurf1 degraded MAVS in MDBK cells in a ubiquitination-dependent manner, ultimately inhibiting IFN-I production. Moreover, knocking out DDIT3 promoted the antiviral innate immune response to reduce BVDV replication and pathological changes in mice. These findings provide direct insights into the molecular mechanisms by which DDIT3 inhibits IFN-I production by regulating MAVS degradation. IMPORTANCE Extensive studies have demonstrated roles of DDIT3 in apoptosis and autophagy during viral infection. However, the role of DDIT3 in innate immunity remains largely unknown. Here, we show that DDIT3 is positively regulated in bovine viral diarrhea virus (BVDV)-infected Madin-Darby bovine kidney (MDBK) cells and could significantly enhance BVDV replication. Importantly, DDIT3 induced OTU deubiquitinase 1 (OTUD1) expression by activating the NF-κB signaling pathway, thus increasing intracellular Smurf1 protein levels to degrade MAVS and inhibit IFN-I production during BVDV infection. Together, these results indicate that DDIT3 plays critical roles in host innate immunity repression and viral infection facilitation.