PXD071786-1

PXD071786 is an original dataset announced via ProteomeXchange.

Title	Role of p38α MAPK in Monkeypox Virus Replication and Neuroinvasion: Implications for Therapeutic Targeting
Description	Monkeypox virus (MPXV), a re-emerging zoonotic orthopoxvirus, has been increasingly linked to neurological manifestations in both patients and in experimental models. However, the mechanisms underlying MPXV-induced neural injury remain unclear. In non-human primate (NHP) model, we observed MPXV replication across multiple brain regions beginning at 7 days post-infection (dpi), peaking in the medulla oblongata at 14 dpi, and largely clearing by 21 dpi. Viral RNA was detected in the choroid plexus and cerebral microvascular endothelium, suggesting MPXV crosses the blood-brain barrier (BBB) via vascular routes. MPXV infected various neural cell types, including neurons, astrocytes, microglia, and neural stem cells, triggering neuroinflammatory responses. In human pluripotent stem cell (iPSC)-derived neural progenitor cells, neurons, and astrocytes, productive MPXV infection was demonstrate across all cell types. Astrocytes exhibited dose-dependent susceptibility and pro-inflammatory cytokine induction. Transcriptomic analysis revealed the activation of the MAPK signaling pathway. Through CRISPR-Cas9 screening, we identified p38 MAPK as a key regulator of MPXV replication. Pharmacological inhibition of p38 MAPK (SB203580, VX-745) significantly reduced viral replication and pro-inflammatory cytokine production across various cell models, including glioblastoma cells, primary astrocytes, A549 epithelial cells, and brain organoids. Mechanistically, p38 MAPK phosphorylated the viral envelope protein VP37 at T220, enhancing its membrane association and trans-Golgi network localization, thereby facilitating viral maturation. Additionally, p38 MAPK suppressed STING phosphorylation and downstream interferon signaling, aiding immune evasion. Extending these findings, p38 MAPK activity was found to be essential for vaccinia virus (VACV-VG9) replication. Collectively, our study uncovers p38 MAPK as a central host dependency factor for MPXV replication and neuroinflammation, highlighting p38 inhibition as a promising broad-spectrum antiviral strategy. These findings not only provide mechanistic insights into MPXV neuropathogenesis but also identify a clinically actionable therapeutic target with potential efficacy against multiple poxvirus infections.
HostingRepository	iProX
AnnounceDate	2025-12-09
AnnouncementXML	Submission_2025-12-09_17:35:37.085.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zhengcun Wu
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-09 17:35:00	ID requested
⏵ 1	2025-12-09 17:35:37	announced

Dataset with its publication pending

submitter keyword: Monkeypox (MPXV), Neuroinvasion, p38α, VP37, STING

Qiangming Sun
contact affiliation	Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan Province, China
contact email	qsun@imbcams.com.cn
lab head
Zhengcun Wu
contact affiliation	Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan Province, China
contact email	wzc1121@imbcams.com.cn
dataset submitter

iProX dataset URI