MAML1‐induced HPV E6 oncoprotein stability is required for cellular proliferation and migration of cervical tumor‐derived cells

Skelin, Josipa; Đukić, Anamaria; Filić, Vedrana; Hufbauer, Martin; Akgül, Baki; Thomas, Miranda; Banks, Lawrence; Tomaić, Vjekoslav (2023) MAML1‐induced HPV E6 oncoprotein stability is required for cellular proliferation and migration of cervical tumor‐derived cells. Journal of Medical Virology, 95 (3). ISSN 0146-6615

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Abstract

While a small proportion of high-risk (HR) alpha (α) human papillomaviruses (HPVs) is associated with numerous human malignancies, of which cervical cancer is the most prevalent, beta (β) HPVs predominantly act as co-factors in skin carcinogenesis. A characteristic feature of both α- and β-E6 oncoproteins is the presence of the LXXLL binding motif, which α-E6s utilize to form a complex with E6AP and which enables β-E6s to interact with MAML1. Here we show that multiple α-E6 oncoproteins bind to MAML1 via the LXXLL binding motif and that this results in increased protein stability. Moreover, β-E6 oncoprotein stability is also dependent on the interaction with MAML1. Additionally, in the absence of MAML1, endogenous HPV-8 E6 and HPV-18 E6 are rapidly degraded at the proteasome. Ablation of both E6AP and MAML1 leads to an even more profound downregulation of α-E6 protein expression, whereas this is not observed with β-E6. This highly suggests that there is one cellular pool for most of β-E6 that interacts solely with MAML1, whereas there are two cellular pools of HR α-E6, one forming a complex with MAML1 and the other interacting with E6AP. Furthermore, MAML1 induces HPV-8 E6 shuttling from the nucleus to the cytosolic fraction, while MAML1 interaction with HR E6 induces a drastic nuclear and membrane upregulation of E6. Interestingly, the HR α-E6/MAML1 complex does not affect targeting of some of the known HR E6 cellular substrates such as p53 and DLG1. However, MAML1 and E6AP joint co-expression with HR α-E6 leads to a significant increase in cellular proliferation, whereas silencing MAML1 decreases wound closure in HeLa cells. These results demonstrate that HR α-E6 interaction with MAML1 results in a stable form of E6, which likely modulates MAML1's normal cellular activities, one consequence of which being an increased proliferative capacity of HPV-transformed cancer cells. Thus, this study shows a novel function of the α-E6 oncoprotein and how it's activity might affect HPV-induced pathogenesis.

Item Type:	Article
Uncontrolled Keywords:	E6; E6AP; HPV; MAML1; cervical cancer; migration; oncogenesis; proliferation; skin cancer
Subjects:	BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions:	Division of Molecular Medicine
Depositing User:	Vjekoslav Tomaić
Date Deposited:	05 Feb 2024 09:26
URI:	http://fulir.irb.hr/id/eprint/8431
DOI:	10.1002/jmv.28624

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