2025-11-12 東京大学
ウイルス因子と宿主因子の協調作用によるHAMの炎症増幅サイクル
<関連情報>
- https://www.k.u-tokyo.ac.jp/information/category/press/0028388.html
- https://www.k.u-tokyo.ac.jp/assets/files/HTLV-1感染が宿主細胞の遺伝子発現の設計図を再構築_WEB.pdf
- https://www.nature.com/articles/s41467-025-64836-7
クロマチンリモデリングはHAMにおけるMAP3K8の発現を促進する:治療介入の重要な病因 Chromatin remodeling enhances MAP3K8 expression in HAM: a key pathogenesis for therapeutic intervention
Makoto Nakashima,Kaho Nagai,Naoki Takao,Natsumi Araya,Yuuta Kuze,Jun Mizuike,Shu Tosaka,Satoko Aratani,Naoko Yagishita,Erika Horibe,Toshiki Watanabe,Tomoo Sato,Yasuhito Nannya,Yutaka Suzuki,Kaoru Uchimaru,Makoto Yamagishi & Yoshihisa Yamano
Nature Communications Published:10 November 2025
DOI:https://doi.org/10.1038/s41467-025-64836-7
Abstract
Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM) is a debilitating neuroinflammatory disease with no available effective treatments. A hallmark of HAM is the transformation of HTLV-1-infected cells into T helper type 1 (Th1)-like cells, characterized by excessive interferon (IFN)-γ production that drives chronic inflammation. However, the molecular mechanisms fuel this aberrant Th1-like transformation and sustained inflammation remain poorly understood. We hypothesized that HAM-characteristic chromatin remodeling plays a pivotal role in the overexpression of key genes driving inflammatory pathogenesis. Using transcriptomic analysis, chromatin accessibility profiling, and biomarker evaluations across HTLV-1-related diseases, we identify MAP3K8 as a key gene that defines the unique inflammatory profile of HAM. MAP3K8 overexpression promotes Th1-like differentiation and constitutively activates the MEK-ERK signaling pathway. Furthermore, we elucidate the mechanism by which HTLV-1 Tax, Fosl2, and c-Jun collaboratively induce HAM-characteristic chromatin remodeling at the enhancer region of the MAP3K8 locus. Crucially, we demonstrate that mitogen-activated protein kinase kinase (MEK) inhibitors effectively suppress the MAP3K8-MEK signaling cascade and significantly mitigated inflammatory pathogenesis in an ex vivo culture assay. Our findings provide critical insights into the virus-host interactions underpinning HAM and propose the MAP3K8-MEK-ERK axis as a promising therapeutic target for this challenging condition.
