MAML1‐induced HPV E6 oncoprotein stability is required for cellular proliferation and migration of cervical tumor‐derived cells. Issue 3 (14th March 2023)

• Record Type: Journal Article
• Authors: Skelin, Josipa; Đukić, Anamaria; Filić, Vedrana; Hufbauer, Martin; Akgül, Baki; Thomas, Miranda; Banks, Lawrence; Tomaić, Vjekoslav
• Is Part Of: Journal of medical virology. Volume 95:Issue 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-03-14
• Subjects: cervical cancer -- E6 -- E6AP -- HPV -- MAML1 -- migration -- oncogenesis -- proliferation -- skin cancer; Virology -- Periodicals; 616
• DOI: 10.1002/jmv.28624
• Languages: English
• ISSNs: 0146-6615

Abstract

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.