Phosphorylated HPV‑16 E7 disrupts planar cell polarity in cervical cancer cells through vangl1 dysregulation
5 affiliations
- 1Tumour Virology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
- 2Protein Networks, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
- 3Cancer Cell Signalling, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
- 4Department of Life Science, University of Trieste, Trieste, Italy
- 5IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
Abstract
High‑risk (HR) human papillomaviruses (HPVs) rely on the continuous expression of the E6 and E7 oncoproteins to reshape epithelial biology, drive and sustain malignant transformation. The high‑risk E7 oncoprotein is multifunctional, and its phosphorylation by Casein Kinase II (CKII) is a key post translational modification that amplifies its oncogenic potential. Therefore, it is important to extensively delineate the consequences of E7 phosphorylation on HPV-driven transformation and malignant progression. Here, we identify Vangl1, a core planar cell polarity (PCP) scaffold protein, as a novel, phosphorylation‑dependent interactor of HPV‑16 E7. Through proteomics, biochemical and cell-based assays, this study established that CKII‑mediated phosphorylation is required for Vangl1 recruitment, and that this interaction is more pronounced with HPV‑16 E7, revealing a new mechanism by which HR HPVs might disrupt epithelial organization. In CaSki cells and ectopic expression models, E7 expression profoundly disrupts Vangl1 homeostasis, creating a biphasic proteostatic imbalance in which phosphorylated Vangl1 is aberrantly stabilised. This retention parallels E7 stability, revealing a reciprocal oncogenic stabilization. Furthermore, we found that Vangl1 is depleted in cytoskeletal cell fractions in the presence of E7, and that E7 translocates to membrane compartments where it colocalizes with Vangl1. In line with this, we identified that this abnormal Vangl1 stabilization occurs from its mislocalization and impaired trafficking arising from E7’s interference with the Adaptor-Related Protein Complex 1 Subunit Mu 1 (AP1M1). Functionally, Vangl1 siRNA-mediated ablation in CaSki spheroids mirrors E6/E7 loss, leading to disrupted spheroidal architecture, reduced invasion, and increased sensitivity to chemotherapeutic stress. These phenotypes position Vangl1 as a key downstream effector through which E7 reshaped epithelial behaviour. Taken together, our findings reveal a CKII-dependent mechanism by which HPV-16 E7 hijacks a core planar polarity component to destabilize epithelial structure and promote malignant traits; thus, positioning Vangl1 as a potential druggable target in HPV-associated cervical cancer. Author summary: High-risk human papillomaviruses (HPVs) cause most cervical cancers. These viruses rely on the continuous expression of their E6 and E7 oncoproteins to reprogramme infected cells and promote cancer progression. Previous studies show that the oncogenic activity of E7 is strengthened by phosphorylation by Casein Kinase II (CKII), suggesting that this modification may enable E7 to engage specific host factors. In this study, we explored host cellular factors that specifically interact with the phosphorylated form of E7. We found that CKII-phosphorylated HPV-16 E7 binds to Vangl1, a key regulator of planar cell polarity. This interaction disrupts Vangl1’s normal trafficking, turnover, and localization, causing its abnormal distribution inside cells. The resulting imbalance destabilizes epithelial organization. When we reduced Vangl1 expression in HPV-positive cancer cells, they lost their invasive architecture and became more sensitive to chemotherapy similar to the effects of E6/E7 loss. Our findings reveal a novel mechanism by which HPV-16 dysregulates planar polarityto promote malignant characteristics, and identify Vangl1 modulation as a potential therapeutic approach.
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BibTeX
@article{gbala2026phosphorylated,
title = {{Phosphorylated HPV‑16 E7 disrupts planar cell polarity in cervical cancer cells through vangl1 dysregulation}},
author = {Ifeoluwa D. Gbala and Om Basukala and Amira Zine El Abidine and Michael P. Myers and Rebecca Bertolio and Giannino Del Sal and Lawrence Banks},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014555},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014555},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Phosphorylated HPV‑16 E7 disrupts planar cell polarity in cervical cancer cells through vangl1 dysregulation
AU - Ifeoluwa D. Gbala
AU - Om Basukala
AU - Amira Zine El Abidine
AU - Michael P. Myers
AU - Rebecca Bertolio
AU - Giannino Del Sal
AU - Lawrence Banks
PY - 2026
DA - 2026/09/21
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014555
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014555
AB - High‑risk (HR) human papillomaviruses (HPVs) rely on the continuous expression of the E6 and E7 oncoproteins to reshape epithelial biology, drive and sustain malignant transformation. The high‑risk E7 oncoprotein is multifunctional, and its phosphorylation by Casein Kinase II (CKII) is a key post translational modification that amplifies its oncogenic potential. Therefore, it is important to extensively delineate the consequences of E7 phosphorylation on HPV-driven transformation and malignant progression. Here, we identify Vangl1, a core planar cell polarity (PCP) scaffold protein, as a novel, phosphorylation‑dependent interactor of HPV‑16 E7. Through proteomics, biochemical and cell-based assays, this study established that CKII‑mediated phosphorylation is required for Vangl1 recruitment, and that this interaction is more pronounced with HPV‑16 E7, revealing a new mechanism by which HR HPVs might disrupt epithelial organization. In CaSki cells and ectopic expression models, E7 expression profoundly disrupts Vangl1 homeostasis, creating a biphasic proteostatic imbalance in which phosphorylated Vangl1 is aberrantly stabilised. This retention parallels E7 stability, revealing a reciprocal oncogenic stabilization. Furthermore, we found that Vangl1 is depleted in cytoskeletal cell fractions in the presence of E7, and that E7 translocates to membrane compartments where it colocalizes with Vangl1. In line with this, we identified that this abnormal Vangl1 stabilization occurs from its mislocalization and impaired trafficking arising from E7’s interference with the Adaptor-Related Protein Complex 1 Subunit Mu 1 (AP1M1). Functionally, Vangl1 siRNA-mediated ablation in CaSki spheroids mirrors E6/E7 loss, leading to disrupted spheroidal architecture, reduced invasion, and increased sensitivity to chemotherapeutic stress. These phenotypes position Vangl1 as a key downstream effector through which E7 reshaped epithelial behaviour. Taken together, our findings reveal a CKII-dependent mechanism by which HPV-16 E7 hijacks a core planar polarity component to destabilize epithelial structure and promote malignant traits; thus, positioning Vangl1 as a potential druggable target in HPV-associated cervical cancer. Author summary: High-risk human papillomaviruses (HPVs) cause most cervical cancers. These viruses rely on the continuous expression of their E6 and E7 oncoproteins to reprogramme infected cells and promote cancer progression. Previous studies show that the oncogenic activity of E7 is strengthened by phosphorylation by Casein Kinase II (CKII), suggesting that this modification may enable E7 to engage specific host factors. In this study, we explored host cellular factors that specifically interact with the phosphorylated form of E7. We found that CKII-phosphorylated HPV-16 E7 binds to Vangl1, a key regulator of planar cell polarity. This interaction disrupts Vangl1’s normal trafficking, turnover, and localization, causing its abnormal distribution inside cells. The resulting imbalance destabilizes epithelial organization. When we reduced Vangl1 expression in HPV-positive cancer cells, they lost their invasive architecture and became more sensitive to chemotherapy similar to the effects of E6/E7 loss. Our findings reveal a novel mechanism by which HPV-16 dysregulates planar polarityto promote malignant characteristics, and identify Vangl1 modulation as a potential therapeutic approach.
SN - 1553-7374
ER -