虽然少部分高风险（HR）α人乳头瘤病毒（HPV）与多种人类恶性肿瘤有关，其中颈部癌最为普遍，但β-HPV主要作为皮肤癌致癌因子。α和β-E6致癌蛋白的一个特征是存在LXXLL结合基序，α-E6利用它与E6AP形成复合物，使β-E6能够与MAML1相互作用。我们在此展示，多种α-E6致癌蛋白通过LXXLL结合基序与MAML1结合，导致蛋白稳定性增加。此外，β-E6致癌蛋白的稳定性也依赖于与MAML1的相互作用。 此外，在没有MAML1的情况下，内源性HPV-8 E6和HPV-18 E6会在蛋白酶体中迅速降解。去除E6AP和MAML1会导致α-E6蛋白表达更明显下调，而β-E6不会。这高度暗示了β-E6与MAML1独自相互作用的大部分β-E6细胞库，而HR α-E6有两个细胞库，一个与MAML1形成复合物，另一个与E6AP相互作用。此外，MAML1会导致HPV-8 E6从细胞核穿梭到细胞质分数，而MAML1与HR E6的相互作用会导致E6的明显核膜上调。有趣的是，HR α-E6 / MAML1复合物不会影响已知HR E6细胞底物p53和DLG1的靶向。但是，MAML1和E6AP与HR α-E6的共同表达会导致细胞分裂能力显著增加，而沉默MAML1则减少HeLa细胞的伤口愈合。这些结果表明，HR α-E6与MAML1的相互作用会导致E6的稳定形式，这很可能会调节MAML1的正常细胞活动，其中之一是增加HPV转化的癌细胞的增殖能力。因此，这项研究展示了α-E6致癌蛋白的新功能，以及它的活性如何影响HPV诱导的病理生理过程。本文受版权保护。版权所有。

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 down-regulation 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. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.