Vinueza Joselyn Landazuri, Salisbury Nicholas J H, Dye Kristine N, Roman Ann, Galloway Denise A
Department of Microbiology, University of Washington, Seattle, WA, 98109, USA.
Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, 98109 USA.
bioRxiv. 2025 Mar 14:2025.03.12.642815. doi: 10.1101/2025.03.12.642815.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast, cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that LSD1 (KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.
默克尔细胞癌（MCC）是一种侵袭性很强的神经内分泌皮肤癌，通常由默克尔细胞多瘤病毒（MCPyV）整合到宿主基因组中并持续表达其病毒癌蛋白、小肿瘤（ST）抗原和截短的大肿瘤（t-LT）抗原所驱动。虽然人类成纤维细胞支持MCPyV复制，但MCC的起源细胞仍不清楚。我们推测MCPyV最初在成纤维细胞中复制，但在极少数情况下会感染默克尔细胞祖细胞，从而导致MCC的发生。通过TurboID质谱分析，我们在成纤维细胞中鉴定出δ-连环蛋白是一种新的ST相互作用蛋白。然而，虽然ST在成纤维细胞中与δ-连环蛋白结合，但在病毒阳性（VP）-MCC细胞系中这种相互作用不存在。尽管如此，δ-连环蛋白对VP-MCC至关重要，但对成纤维细胞的增殖并非必需。我们发现成纤维细胞主要表达δ-连环蛋白亚型1，而VP-MCC细胞主要表达亚型3。在VP-MCC中过表达亚型1未能恢复ST结合。δ-连环蛋白通过与转录抑制因子Kaiso相互作用调节细胞周期基因表达，从而促进VP-MCC增殖。此外，我们发现赖氨酸特异性去甲基化酶1（LSD1，KDM1A）通过调节δ-连环蛋白剪接因子ESRP1来调节δ-连环蛋白亚型3的表达。我们的研究结果揭示了参与MCPyV感染和MCC肿瘤发生的新宿主因子，表明支持病毒复制的宿主细胞和MCC的起源细胞可能是不同的细胞类型。
