Epidermal Growth Factor Receptor and Abl2 Kinase Regulate Distinct Steps of Human Papillomavirus 16 Endocytosis
Epidermal Growth Factor Receptor and Abl2 Kinase Regulate Distinct Steps of Human Papillomavirus 16 Endocytosis
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DOI：
10.1128/jvi.02143-19
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发表时间：
2020-06-01
影响因子：
5.4
通讯作者：
Schelhaas, Mario
中科院分区：
文献类型：
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作者：
Bannach, Carina;Brinkert, Pia;Schelhaas, Mario
人乳头瘤病毒 16 (HPV16) 是宫颈癌的主要原因，在进入宿主细胞期间利用了一种新的内吞途径。该机制与巨胞饮作用有许多共同的要求，但在囊泡形成模式上有所不同。先前的研究表明表皮生长因子受体 (EGFR) 在 HPV16 内吞作用中发挥作用。然而，HPV16 摄取过程中 EGFR 信号传导及其下游靶点的功能结果尚未得到很好的表征。在这里，我们分析了通过 EGFR 及其下游效应器进行信号转导对于 HPV16 内吞作用的功能重要性。我们的研究结果表明 EGFR 信号传导有两个阶段，如下：细胞结合时或细胞结合后不久的可能可有可无的瞬时激活以及 HPV16 异步内化过程中所需的信号传导。有趣的是，EGFR 抑制干扰病毒内化并强烈减少内吞坑的数量，表明 EGFR 信号传导在诱导 HPV16 内吞作用中发挥作用。此外，我们还发现 Src 相关激酶 Abl2 是病毒摄取的新型调节因子。 Abl2 的抑制导致畸形内吞凹坑的积累，表明 Abl2 对于内吞囊泡成熟的重要性。由于巨胞饮过程中膜波动的调节因子 Abl2 而不是 Src 介导 EGFR 下游信号传导，因此我们提出靶向 EGFR 下游的选择性效应器决定是否诱导 HPV16 胞吞作用或巨胞饮作用。 重要性 人乳头瘤病毒是感染皮肤和粘膜的小型无包膜 DNA 病毒。所谓的高危HPV（例如HPV16、HPV18、HPV31）具有转化潜力，并与各种肛门生殖器和口咽肿瘤相关。这些病毒通过具有未知细胞功能的新型内吞途径进入宿主细胞。迄今为止，尚不清楚内吞囊泡形成的机制是如何发生的。在这里，我们探讨了表皮生长因子受体信号传导的作用，该信号先前与 HPV16 内吞作用有关，并确定激酶 Abl2 是病毒摄取的新型调节剂。由于其他病毒，例如甲型流感病毒和淋巴细胞性脉络丛脑膜炎病毒，可能利用相关机制，因此我们的研究结果揭示了病毒进入的基本策略，进而可能有助于开发新的靶向宿主细胞的抗病毒策略。
Human papillomavirus 16 (HPV16), the leading cause of cervical cancer, exploits a novel endocytic pathway during host cell entry. This mechanism shares many requirements with macropinocytosis but differs in the mode of vesicle formation. Previous work indicated a role of the epidermal growth factor receptor (EGFR) in HPV16 endocytosis. However, the functional outcome of EGFR signaling and its downstream targets during HPV16 uptake are not well characterized. Here, we analyzed the functional importance of signal transduction via EGFR and its downstream effectors for endocytosis of HPV16. Our findings indicate two phases of EGFR signaling as follows: a-likely dispensable-transient activation with or shortly after cell binding and signaling required throughout the process of asynchronous internalization of HPV16. Interestingly, EGFR inhibition interfered with virus internalization and strongly reduced the number of endocytic pits, suggesting a role for EGFR signaling in the induction of HPV16 endocytosis. Moreover, we identified the Src-related kinase Abl2 as a novel regulator of virus uptake. Inhibition of Abl2 resulted in an accumulation of misshaped endocytic pits, indicating Abl2's importance for endocytic vesicle maturation. Since Abl2 rather than Src, a regulator of membrane ruffling during macropinocytosis, mediated downstream signaling of EGFR, we propose that the selective effector targeting downstream of EGFR determines whether HPV16 endocytosis or macropinocytosis is induced.IMPORTANCE Human papillomaviruses are small, nonenveloped DNA viruses that infect skin and mucosa. The so-called high-risk HPVs (e.g., HPV16, HPV18, HPV31) have transforming potential and are associated with various anogenital and oropharyngeal tumors. These viruses enter host cells by a novel endocytic pathway with unknown cellular function. To date, it is unclear how endocytic vesicle formation occurs mechanistically. Here, we addressed the role of epidermal growth factor receptor signaling, which has previously been implicated in HPV16 endocytosis and identified the kinase Abl2 as a novel regulator of virus uptake. Since other viruses, such as influenza A virus and lymphocytic choriomeningitis virus, possibly make use of related mechanisms, our findings shed light on fundamental strategies of virus entry and may in turn help to develop new host cell-targeted antiviral strategies.