伪狂犬病毒 UL13 通过下调热休克因子 1 激发炎症反应。

IF 2.8 3区 医学 Q3 VIROLOGY Virology Pub Date : 2024-08-31 DOI:10.1016/j.virol.2024.110214
Wen-Jing Zhang, Han Feng, Mei-Mei Zhang, Jing-Song Liu, Lin-Tao Li, Huan-Chun Chen, Zheng-Fei Liu
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引用次数: 0

摘要

伪狂犬病毒是一种猪α-疱疹病毒。我们证实,α-疱疹病毒感染会下调热休克反应中的主转录因子 HSF1。病毒晚期蛋白 UL13 的丝氨酸/苏氨酸蛋白激酶活性对于 HSF1 的耗竭和磷酸化不可或缺,而且 UL13 不会在翻译后降解 HSF1,但会抑制 HSF1 mRNA 水平。重要的是,UL13虽然降低了HSF1 mRNA,但却增加了HSF1的活性。此外,在 HSF1 基因敲除细胞系中或在 HSF1 特异性抑制剂存在的情况下,病毒复制明显减少。有趣的是,HSF1 基因敲除加速了 NF-κB 和 p38MAPK 的激活。UL13的K96位点对诱导高水平的IL-6、TNF-α和IL-β细胞因子非常重要,同时在促进轻度间质性肺炎、肝坏死和脚垫严重炎症细胞浸润方面起着至关重要的作用。因此,UL13 引导热休克反应,促进病毒复制和炎症反应。重要性:PRV 是一种无处不在的病原体,可感染多种哺乳动物,如猪、反刍动物、肉食动物、啮齿动物以及人类,给养猪业造成了巨大的经济损失。在此,我们以 PRV 为模型来确定 α-疱疹病毒与炎症反应之间的关系。总之,我们的研究结果表明,PRV 感染会通过 UL13 的丝氨酸/苏氨酸蛋白激酶活性抑制 HSF1 mRNA 的水平。此外,我们还发现 HSF1 参与了 PRV 感染后 NF-κB 的激活。PRV UL13 可协调 HSF1 mRNA 水平、HSF1 蛋白磷酸化以及炎症反应的启动。我们的研究揭示了 UL13 血清/苏氨酸蛋白激酶活性促进炎症反应的新机制,为治疗阿尔法疱疹病毒感染提供了新线索。
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Pseudorabies virus UL13 primes inflammatory response through downregulating heat shock factor 1

Pseudorabies virus is a swine alpha-herpesvirus. We demonstrated that alpha-herpesvirus infection downregulates HSF1, a master transcription factor in the heat shock response. The serine/threonine protein kinase activity of late viral protein UL13 is indispensable for HSF1 depletion and phosphorylation, and UL13 does not degrade HSF1 posttranslationally but inhibits the HSF1 mRNA level. Importantly, UL13 increased HSF1 activity even though it reduced HSF1 mRNA. Furthermore, viral replication markedly decreased in the HSF1 knockout cell line or in the presence of an HSF1-specific inhibitor. Interestingly, HSF1 knockout accelerated the activation of NF-κB and p38MAPK. The K96 loci of UL13 are important to induce high levels of IL-6, TNF-α, and IL-β cytokines while playing a crucial role in promoting mild interstitial pneumonia, liver necrosis, and severe inflammatory cell infiltration in the footpad. Thus, UL13 steers the heat shock response to promote viral replication and the inflammatory response.

Importance

PRV is a ubiquitous pathogen that infects a variety of mammals, such as pigs, ruminants, carnivores, and rodents as well as human beings, causing enormous economic losses in the swine industry. Here, we employed PRV as a model to determine the relationship between α-herpesvirus and the inflammatory response. Overall, our findings indicated that PRV infection inhibits the level of HSF1 mRNA via the serine/threonine protein kinase activity of UL13. Additionally, we discovered that HSF1 was involved in NF-κB activation upon PRV infection. PRV UL13 orchestrates the level of HSF1 mRNA, HSF1 protein phosphorylation, and priming of the inflammatory response. Our study reveals a novel mechanism employed by UL13 serine/threonine protein kinase activity to promote the inflammatory response, providing novel clues for therapy against alpha-herpesvirus infection.

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来源期刊
Virology
Virology 医学-病毒学
CiteScore
6.00
自引率
0.00%
发文量
157
审稿时长
50 days
期刊介绍: The journal features articles on virus replication, virus-host biology, viral pathogenesis, immunity to viruses, virus structure, and virus evolution and ecology. We aim to publish papers that provide advances to the understanding of virus biology.
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