Sp140L functions as a herpesvirus restriction factor suppressing viral transcription and activating interferon- stimulated genes
Author(s)
Cable, Jana M
Wongwiwat, Wiyada
Grabowski, Jenna C
White, Robert E
Luftig, Micah A
Type
Journal Article
Abstract
Herpesviruses, including Epstein–Barr virus (EBV) – a human oncogenic virus and essential trigger of multiple sclerosis – must bypass host DNA-sensing mechanisms to establish lifelong, latent infection. Therefore, herpesviruses encode viral proteins to disrupt key host factors involved in DNA sensing and viral restriction. The first viral latency protein expressed, EBNA-LP, is essential for transformation of naïve B cells and establishment of viral gene expression, yet its role in evading host defenses remains unclear. Using single-cell RNA sequencing of EBNA-LP Knockout (LPKO)-infected B cells, we reveal an antiviral response landscape implicating the “speckled proteins” as key cellular restriction factors countered by EBNA-LP. Specifically, loss of Sp100 or the primate-specific Sp140L reverses the restriction of LPKO, suppresses a subset of canonically interferon-stimulated genes, and restores transcription of essential latent viral genes and cellular proliferation. Notably, we also identify Sp140L as a restriction target of the herpesvirus saimiri ORF3 protein, implying a role for Sp140L in immunity to other diverse DNA viruses. This study reveals Sp140L as a restriction factor that we propose links sensing and transcriptional suppression of viral DNA to an Interferon-independent innate immune response, likely relevant to all nuclear DNA viruses.
Date Issued
2025-06-24
Date Acceptance
2025-04-29
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2025, 122 (25)
ISSN
0027-8424
Publisher
National Academy of Sciences
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
122
Issue
25
Copyright Statement
© 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40526717
Subjects
DAXX
DEGRADATION
DNA
DNA sensing
Epstein-Barrvirus
EXPRESSION
herpesvirus
HISTONE H3
HUMAN CYTOMEGALOVIRUS
Multidisciplinary Sciences
NUCLEAR-BODIES
PML nuclear bodies
PROTEIN EBNA-LP
Science & Technology
Science & Technology - Other Topics
SIMPLEX-VIRUS TYPE-1
SP100
speckled proteins
Publication Status
Published
Coverage Spatial
United States
Article Number
e2426339122
Date Publish Online
2025-06-17