| RRC ID |
86854
|
| Author |
Nakashima M, Nagai K, Takao N, Araya N, Kuze Y, Mizuike J, Tosaka S, Aratani S, Yagishita N, Horibe E, Watanabe T, Sato T, Nannya Y, Suzuki Y, Uchimaru K, Yamagishi M, Yamano Y.
|
| Title |
Chromatin remodeling enhances MAP3K8 expression in HAM: a key pathogenesis for therapeutic intervention.
|
| Journal |
Nat Commun
|
| 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.
|
| Volume |
16(1)
|
| Pages |
9874
|
| Published |
2025-11-10
|
| DOI |
10.1038/s41467-025-64836-7
|
| PII |
10.1038/s41467-025-64836-7
|
| PMID |
41213906
|
| PMC |
PMC12603273
|
| MeSH |
Cell Differentiation
Chromatin Assembly and Disassembly* / genetics
Gene Products, tax / genetics
Gene Products, tax / metabolism
Human T-lymphotropic virus 1*
Humans
MAP Kinase Kinase Kinases* / genetics
MAP Kinase Kinase Kinases* / metabolism
MAP Kinase Signaling System
Paraparesis, Tropical Spastic* / genetics
Paraparesis, Tropical Spastic* / immunology
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-fos / genetics
Proto-Oncogene Proteins c-fos / metabolism
Th1 Cells / immunology
Th1 Cells / metabolism
|
| IF |
12.121
|
| Resource |
| DNA material |
CSII-EF-MCS-IRES2-Venus (RDB04384)
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
