MITA oligomerization upon viral infection is dependent on its N-glycosylation mediated by DDOST.
MITA oligomerization upon viral infection is dependent on its N-glycosylation mediated by DDOST.
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DOI：
10.1371/journal.ppat.1010989
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发表时间：
2022-11
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
IRF 3激活介体（mediator of IRF 3 activation，MITA，也称为STING）对于针对异常胞质DNA的免疫应答至关重要，并且已被认为是肿瘤和自身免疫性疾病的临床治疗中的重要药物靶标。在本研究中，我们报告说，MITA经历DDOST介导的N-糖基化的内质网（ER）DNA病毒感染后。DDOST依赖性N-糖基化残基的选择性突变消除了MITA寡聚化，从而消除了其免疫功能。此外，增加Ddost在小鼠脑中的表达有效地增强了对单纯疱疹病毒-1（HSV-1）的局部免疫应答，并延长了患有HSV脑炎（HSE）的小鼠的存活时间。我们的研究结果揭示了N-糖基化对MITA激活的依赖性，并为HSE的发病机制提供了新的视角。干扰素（IFN）在控制病毒感染中起关键作用。IFN产生不足导致慢性感染和疾病进展。在这里，我们报告说，DDOST是一个重要的调节MITA/STING介导的生产抗病毒I型干扰素。DDOST敲低损害MITA介导的IFN对HSV-1和双链DNA（dsDNA）的应答。从机制上讲，DDOST介导HSV-1诱导的MITA在某些残基的N-糖基化，这对促进MITA寡聚化和随后的免疫功能至关重要。此外，内源性DDOST的表达在脑中特别低。增加Ddost在小鼠脑组织中的表达可增强局部免疫功能，延长HSE小鼠的生存时间。这些发现揭示了MITA寡聚化的调控机制，为HSE的发病机制提供了一种解释，为开发新的抗病毒药物提供了线索。
The mediator of IRF3 activation (MITA, also named STING) is critical for immune responses to abnormal cytosolic DNA and has been considered an important drug target in the clinical therapy of tumors and autoimmune diseases. In the present study, we report that MITA undergoes DDOST-mediated N-glycosylation in the endoplasmic reticulum (ER) upon DNA viral infection. Selective mutation of DDOST-dependent N-glycosylated residues abolished MITA oligomerization and thereby its immune functions. Moreover, increasing the expression of Ddost in the mouse brain effectively strengthens the local immune response to herpes simplex virus-1 (HSV-1) and prolongs the survival time of mice with HSV encephalitis (HSE). Our findings reveal the dependence of N-glycosylation on MITA activation and provide a new perspective on the pathogenesis of HSE. Interferons (IFNs) play critical roles in controlling viral infection. Insufficient production of IFNs leads to chronic infection and disease progression. Here, we report that DDOST is an important regulator of the MITA/STING-mediated production of antiviral type I IFNs. DDOST knockdown impairs the MITA-mediated IFN response to HSV-1 and double-stranded DNA (dsDNA). Mechanistically, DDOST mediates HSV-1-induced N-glycosylation of MITA at certain residues, which is essential to promote MITA oligomerization and consequent immune functions. Moreover, the expression of endogenous DDOST was specifically low in the brain. Increasing the expression of Ddost in the mouse brain strengthens the local immune functions and prolongs the survival time of mice with HSE. These findings reveal a regulatory mechanism of MITA oligomerization and provide one explanation for the pathogenesis of HSE, which provides a clue for developing a new antiviral drug.
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影响因子：
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作者：
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影响因子：
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影响因子：
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影响因子：
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