School of Life Sciences, Chongqing University, Chongqing, China.
Key Laboratory of Animal Immunology of the Ministry of Agriculture, Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, Henan, China.
J Virol. 2024 May 14;98(5):e0048324. doi: 10.1128/jvi.00483-24. Epub 2024 Apr 19.
Alphaherpesvirus pseudorabies virus (PRV) causes severe economic losses to the global pig industry and has garnered increasing attention due to its broad host range including humans. PRV has developed a variety of strategies to antagonize host antiviral innate immunity. However, the underlying mechanisms have not been fully elucidated. In our previous work, we demonstrated that non-muscle myosin heavy chain IIA (NMHC-IIA), a multifunctional cytoskeleton protein, attenuates innate immune responses triggered by RNA viruses. In the current study, we reported a previously unrecognized role of NMHC-IIA in counteracting PRV-induced cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN-I) production. Mechanistically, PRV infection led to an elevation of NMHC-IIA, strengthening the interaction between poly (ADP-ribose) polymerase 1 (PARP1) and cGAS. This interaction impeded cGAS recognition of PRV DNA and hindered downstream signaling activation. Conversely, inhibition of NMHC-IIA by Blebbistatin triggered innate immune responses and enhanced resistance to PRV proliferation both and . Taken together, our findings unveil that PRV utilizes NMHC-IIA to antagonize host antiviral immune responses via impairing DNA sensing by cGAS. This in-depth understanding of PRV immunosuppression not only provides insights for potential PRV treatment strategies but also highlights NMHC-IIA as a versatile immunosuppressive regulator usurped by both DNA and RNA viruses. Consequently, NMHC-IIA holds promise as a target for the development of broad-spectrum antiviral drugs.IMPORTANCECyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in counteracting alphaherpesvirus infections. Alphaherpesviruses exploit various strategies for antagonizing cGAS-STING-mediated antiviral immune responses. However, limited examples of pseudorabies virus (PRV)-caused immunosuppression have been documented. Our findings reveal a novel role of non-muscle myosin heavy chain IIA (NMHC-IIA) in suppressing PRV-triggered innate immune responses to facilitate viral propagation both and . In detail, NMHC-IIA recruits poly (ADP-ribose) polymerase 1 (PARP1) to augment its interaction with cGAS, which impairs cGAS recognition of PRV DNA. Building on our previous demonstration of NMHC-IIA's immunosuppressive role during RNA virus infections, these findings indicate that NMHC-IIA acts as a broad-spectrum suppressor of host antiviral innate immunity in response to both DNA and RNA viruses. Therefore, NMHC-IIA will be a promising target for the development of comprehensive antiviral strategies.
α疱疹病毒伪狂犬病病毒（PRV）给全球养猪业造成了严重的经济损失，由于其广泛的宿主范围包括人类，因此越来越受到关注。PRV 已经发展出多种策略来拮抗宿主抗病毒先天免疫。然而，其潜在的机制尚未完全阐明。在我们之前的工作中，我们证明了非肌肉肌球蛋白重链 IIA（NMHC-IIA），一种多功能细胞骨架蛋白，可减弱 RNA 病毒引发的先天免疫反应。在本研究中，我们报道了 NMHC-IIA 在拮抗 PRV 诱导的环鸟苷酸-腺苷酸合酶（cGAS）依赖性 I 型干扰素（IFN-I）产生中的一个以前未被认识的作用。在机制上，PRV 感染导致 NMHC-IIA 水平升高，从而增强了多聚（ADP-核糖）聚合酶 1（PARP1）与 cGAS 之间的相互作用。这种相互作用阻碍了 cGAS 对 PRV DNA 的识别，并抑制了下游信号的激活。相反，通过 Blebbistatin 抑制 NMHC-IIA 会触发先天免疫反应，并增强对 PRV 增殖的抵抗力。综上所述，我们的研究结果揭示了 PRV 通过损害 cGAS 对 DNA 的识别，利用 NMHC-IIA 拮抗宿主抗病毒免疫反应。深入了解 PRV 的免疫抑制作用不仅为潜在的 PRV 治疗策略提供了依据，而且还突出了 NMHC-IIA 作为被 DNA 和 RNA 病毒劫持的多功能免疫抑制调节剂的作用。因此，NMHC-IIA 有望成为广谱抗病毒药物的开发靶点。
