TBK1 Isoform Inhibits Grass Carp Reovirus Infection by Targeting the Degradation of Viral Nonstructural Proteins NS80 and NS38.
TBK1 Isoform Inhibits Grass Carp Reovirus Infection by Targeting the Degradation of Viral Nonstructural Proteins NS80 and NS38.
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DOI：
10.4049/jimmunol.2200471
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发表时间：
2022-11
影响因子：
4.4
通讯作者：
Jie Zhang;M. Chang
中科院分区：
文献类型：
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作者：
Jie Zhang;M. Chang
TANK结合激酶1（TBK 1）经历选择性剪接，并且先前报道的TBK 1同种型是RIG-I样受体介导的I型IFN产生的负调节剂。虽然有研究表明，草鱼TBK 1在高和低滴度的草鱼呼肠孤病毒（GCRV）感染中具有相反的作用，但草鱼TBK 1亚型在GCRV感染中的功能尚不清楚。在本研究中，我们发现草鱼TBK 1亚型gcTBK1_tv3与斑马鱼TBK1_tv3有1个氨基酸的差异，在高、低滴度感染条件下，gcTBK1_tv3均能抑制GCRV的复制和感染。Idellus肾细胞gcTBK1_tv3可与GCRV的NS 80和NS 38蛋白共定位并相互作用。此外，gcTBK1_tv3通过泛素-蛋白酶体途径特异性降解GCRV的NS 80和NS 38蛋白。从机制上讲，gcTBK1_tv3分别通过靶向NS 80的Lys 503残基或NS 38的Lys 328残基，促进NS 80或NS 38的降解，以实现K48连接的遍在蛋白化，最终损害细胞质病毒包涵体的产生并限制GCRV复制和感染。总之，我们的研究结果提供了深入了解TBK 1亚型在抗病毒免疫应答中的功能，并证明TBK 1亚型可以靶向GCRV的非结构蛋白，以损害病毒包涵体的形成。
TANK-binding kinase 1 (TBK1) undergoes alternative splicing, and the previously reported TBK1 isoforms are negative regulators of RIG-I-like receptor-mediated type I IFN production. Although a study has suggested that grass carp TBK1 has an opposite effect at high- and low-titer of grass carp reovirus (GCRV) infection, the functions of grass carp TBK1 isoforms in GCRV infection remain unclear. In this study, we show that a TBK1 isoform from grass carp (Ctenopharyngodon idellus) named as gcTBK1_tv3, which has a 1-aa difference with zebrafish TBK1_tv3, inhibits the replication and infection of GCRV both at high and low titers of infection in C. idellus kidney cells. gcTBK1_tv3 can colocalize and interact with the NS80 and NS38 proteins of GCRV. Furthermore, gcTBK1_tv3 specifically degrades the NS80 and NS38 proteins of GCRV through the ubiquitin-proteasome pathway. Mechanistically, gcTBK1_tv3 promotes the degradation of NS80 or NS38 for K48-linked ubiquitination by targeting the Lys503 residue of NS80 or Lys328 residue of NS38, respectively, which ultimately impairs the production of cytoplasmic viral inclusion bodies and limits GCRV replication and infection. Taken together, our findings provide insight into the function of TBK1 isoform in the antiviral immune response and demonstrate that TBK1 isoform can target the nonstructural proteins of GCRV for impairing the formation of viral inclusion bodies.