Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/- mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.

中文翻译：

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USP44通过去泛素化MITA积极调节对DNA病毒的先天免疫应答。

IRF3激活的介体（MITA，也称为干扰素基因的刺激物，STING）可感知第二个信使环GMP-AMP（cGAMP），该分子在DNA病毒感染后合成，并激活先天的抗病毒免疫应答。已经证明，通过多种翻译后修饰，包括多聚泛素化，可精细地调节MITA的活性。在这项研究中，我们确定了去泛素化酶USP44是MITA的正调节剂。在DNA病毒感染后，USP44被募集到MITA并在K236处从MITA去除K48连接的多聚泛素部分，因此防止MITA受到蛋白酶体介导的降解。USP44缺陷导致加速HSV-1诱导的MITA降解并减少I型干扰素（IFN）和促炎细胞因子的诱导。一致地，Usp44-/-小鼠对HSV-1感染更敏感，这表现为更高的组织病毒滴度，更大的组织损伤和更低的存活率。这些发现表明，USP44在调节针对DNA病毒的先天免疫应答中起特定而关键的作用。