Avian Hepatitis E Virus ORF2 Protein Interacts with Rap1b to Induce Cytoskeleton Rearrangement That Facilitates Virus Internalization

Zhang, Beibei; Fan, Mengnan; Fan, Jie; Luo, Yuhang; Wang, Jie; Wang, Yajing; Liu, Baoyuan; Sun, Yani; Zhao, Qin; Hiscox, Julian A.; Nan, Yuchen

doi:10.1128/spectrum.02265-21

Cited by 8 publications

(15 citation statements)

References 64 publications

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“…It is observed that avian HEV upregulates and activates Rap1 during infection and consequently rearranges the cytoskeleton to promote virus internalization by permissive cells. 49 Our data show that 25HC decreased active Rho GTPases and Rap1 levels in cervical epithelial cells, most likely through its restriction of isoprenoid synthesis (Figure 5D and 6). Our findings support that small GTPase prenylation could be a promising target for HPV infection.…”

Section: Discussionmentioning

confidence: 63%

“…The mechanism of this actin coordination efficacy is correlated with the LIMK/cofilin pathway. It is observed that avian HEV upregulates and activates Rap1 during infection and consequently rearranges the cytoskeleton to promote virus internalization by permissive cells 49 . Our data show that 25HC decreased active Rho GTPases and Rap1 levels in cervical epithelial cells, most likely through its restriction of isoprenoid synthesis (Figure 5D and 6).…”

Section: Discussionmentioning

confidence: 66%

See 1 more Smart Citation

25‐hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

Li,

Hua,

Tian

et al. 2023

Journal of Medical Virology

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Persistent high‐risk human papilloma virus (HR‐HPV) infection is the main risk factor for cervical cancer, threatening women's health. Despite growing prophylactic vaccination, annual cervical cancer cases are still increasing and show a trend of younger onset age. However, therapeutic approaches towards HPV infection are still limited. 25‐hydrocholesterol (25HC) has a wide‐spectrum inhibitory effect on a variety of viruses. To explore efficient interventions to restrict HPV infection at an early time, we applied different pseudoviruses (PsV) to evaluate anti‐HPV efficacy of 25HC. We tested PsV inhibition by 25HC in cervical epithelial‐derived HeLa and C‐33A cells, using high‐risk (HPV16, HPV18, HPV59), possibly carcinogenic (HPV73), and low‐risk (HPV6) HPV PsVs. Then we established murine genital HPV PsV infection models and applied IVIS to evaluate anti‐HPV efficacy of 25HC in vivo. Next, with the help of confocal imaging, we targeted 25HC activity at filopodia upon HPV exposure. After that, we used RNA‐seq and Western blot analysis to investigate (1) how 25HC disturbs actin cytoskeleton remodeling during HPV infection and (2) how prenylation regulates the cytoskeletal remodeling signaling pathway. Our findings suggest that 25HC perturbs F‐actin rearrangement by reducing small GTPase prenylation. In this way, the phenomenon of HPV virion surfing was restricted, leading to failed infection.

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 66%

25‐hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

Li,

Hua,

Tian

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

show abstract

“…The mechanism of this actin coordination efficacy is correlated with the LIMK/cofilin pathway. It is observed that avian HEV upregulates and activates Rap1 during infection and consequently rearranges the cytoskeleton to promote virus internalization by permissive cells (46). Our data show that 25HC decreased active Rho GTPases and Rap1 levels in cervical epithelial cells, most likely through its restriction of isoprenoid synthesis(Figure 5D, Figure 6) .…”

Section: Discussionmentioning

confidence: 65%

25-hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

Chen

Tian

et al. 2023

Preprint

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Persistent high-risk human papilloma virus (HR-HPV) infection is the main risk factor for cervical cancer, threatening women’s health. Despite growing prophylactic vaccination, annual cervical cancer cases are still increasing and show a trend of younger onset age. However, therapeutic approaches towards HPV infection are still limited. 25-hydrocholesterol (25HC) has a wide-spectrum inhibitory effect on a variety of viruses. To explore efficient interventions to restrict HPV infection at an early time, we applied different pseudoviruses (PsV) to evaluate anti-HPV efficacy of 25HC. We tested PsV inhibition by 25HC in cervical epithelial-derived HeLa and C-33A cells, using high-risk (HPV16, HPV18, HPV59), possibly carcinogenic (HPV73), and low-risk (HPV6) HPV PsVs. Then we established murine genital HPV PsV infection models and applied IVIS to evaluate anti-HPV efficacy of 25HC in vivo. Next, with the help of confocal imaging, we targeted 25HC activity at filopodia upon HPV exposure. After that, we used RNA-seq and Western blotting to investigate 1) how 25HC disturbs actin cytoskeleton remodeling during HPV infection and 2) how prenylation regulates the cytoskeletal remodeling signaling pathway. Our findings suggest that 25HC perturbs F-actin rearrangement by reducing small GTPase prenylation. In this way, the phenomenon of HPV virion surfing was restricted, leading to failed infection.

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“…Uncontrolled Rap1b activation is often associated with the occurrence of tumors, especially highly metastatic malignant ones [ 23 ], in which the process of Rap1b-induced regulation of the cytoskeleton is significant [ 24 ]. Nevertheless, cytoskeleton rearrangement occurs during early HSV-1 viral entry, intracellular trafficking, and release and can be hijacked by the viruses to facilitate viral replications such as those of porcine hemagglutinating encephalomyelitis virus (PHEV) [ 25 ], hepatitis E virus (HEV) [ 26 ], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 27 , 28 , 29 ]. However, the impact of Rap1b in regulating cell membranes during viral replication has rarely been assessed aside from its role in the proliferation and migration of hepatitis-B-infected hepatocytes [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

ICP4-Associated Activation of Rap1b Facilitates Herpes Simplex Virus Type I (HSV-1) Infection in Human Corneal Epithelial Cells

Zhang,

Ding,

2023

Viruses

Self Cite

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The strong contribution of RAS-related protein 1b (Rap1b) to cytoskeleton remodeling determines intracellular and extracellular physiological activities, including the successful infection of viruses in permissive cells, but its role in the HSV-1 life cycle is still unclear. Here, we demonstrated that the HSV-1 immediate early (IE) gene ICP4 inhibits protein kinase A (PKA) phosphorylation to induce Rap1b-activation-mediated viral infection. Rap1b activation and membrane enrichment begin at the early stage of HSV-1 infection and remain active during the proliferation period of the virus. Treating the cells with Rap1b small interfering RNA (siRNA) showed a dose-dependent decrease in viral infection levels, but no dose-dependent increase was observed after Rap1b overexpression. Further investigation indicated that the suppression of Rap1b activation derives from phosphorylated PKA and Rap1b mutants with partial or complete prenylation instead of phosphorylation, which promoted viral infection in a dose-dependent manner. Furthermore, the PKA agonist Forskolin disturbed Rap1b activation in a dose-dependent manner, accompanied by a decreasing trend in viral infection. Moreover, the HSV-1 IE gene ICP4 induced PKA dephosphorylation, leading to continuous Rap1b activation, followed by cytoskeleton rearrangement induced by cell division control protein 42 (CDC42) and Ras-related C3 botulinum toxin substrate 1 (RAC1). These further stimulated membrane-triggered physiological processes favoring virus infection. Altogether, we show the significance of Rap1b during HSV-1 infection and uncover the viral infection mechanism determined by the posttranslational regulation of the viral ICP4 gene and Rap1b host protein.

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Avian Hepatitis E Virus ORF2 Protein Interacts with Rap1b to Induce Cytoskeleton Rearrangement That Facilitates Virus Internalization

Abstract: Rap1b is a multifunctional protein that is responsible for cell adhesion, growth, and differentiation. The inactive form of Rap1b is phosphorylated and distributed in the cytoplasm, while active Rap1b is prenylated and loaded with GTP to the cell membrane.

Cited by 8 publications

References 64 publications

25‐hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

25‐hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

25-hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

ICP4-Associated Activation of Rap1b Facilitates Herpes Simplex Virus Type I (HSV-1) Infection in Human Corneal Epithelial Cells

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