The Hao-Fountain syndrome gene USP7 restricts neurotropic orthoflavivirus entry through cell intrinsic control of endosomal dynamics
- 1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Abstract
Neurodevelopmental disorders are increasingly associated with immune phenotypes, including autoinflammation, immunodeficiency, and increased susceptibility to severe infection. To determine whether neurodevelopmental disorders-associated genes exert immune functions, we performed an arrayed siRNA screen targeting 28 genes with nonredundant cellular roles and assessed their effects on Zika virus (ZIKV) infection and innate immune pathways. We identified hits that intrinsically restrict ZIKV infection and modulate inflammatory pathways following infection. We further characterized the antiviral activity of the Hao-Fountain syndrome gene USP7, which potently restricts selected neurotropic orthoflaviviruses. USP7 inhibits ZIKV internalization before viral membrane fusion and genome release into the cytoplasm. Because USP7 plays a role in endosomal tubulation and recycling, we investigated whether endosomal recycling pathways restrict ZIKV infection. We identified the USP7-regulated E3 ubiquitin ligase TRIM27, as well as the recycling-associated Rab GTPases RAB11 and RAB35, as potent regulators of ZIKV infection. Infection assays using cell lines expressing pathogenic USP7 variants and primary fibroblasts from individuals with Hao-Fountain syndrome demonstrated that disease-associated USP7 mutations impair its antiviral activity and increase permissivity to ZIKV infection. These findings are consistent with recent case reports of unusually severe viral infection during early life in individuals with Hao-Fountain syndrome. Collectively, our study identifies endosomal recycling pathways as important intrinsic restriction mechanisms against neurotropic orthoflaviviruses and nominates pathogenic USP7 variation as a candidate inborn error of immunity.
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BibTeX
@misc{bonaventure2026haofountain,
title = {{The Hao-Fountain syndrome gene USP7 restricts neurotropic orthoflavivirus entry through cell intrinsic control of endosomal dynamics}},
author = {B. Bonaventure and K. Reyes and M.-F. Martin and H. Pan and R. B. Richardson and E. Bednarski and A. W. Ashbrook and A. Sowa and W. Janssen and O. Danziger and A. Cupic and L. Miorin and C. M. Rice and J. K. Lim and B. R. Rosenberg and M. J. Evans and J. R. Johnson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.749922},
url = {https://www.biorxiv.org/content/10.64898/2026.09.09.749922v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The Hao-Fountain syndrome gene USP7 restricts neurotropic orthoflavivirus entry through cell intrinsic control of endosomal dynamics
AU - B. Bonaventure
AU - K. Reyes
AU - M.-F. Martin
AU - H. Pan
AU - R. B. Richardson
AU - E. Bednarski
AU - A. W. Ashbrook
AU - A. Sowa
AU - W. Janssen
AU - O. Danziger
AU - A. Cupic
AU - L. Miorin
AU - C. M. Rice
AU - J. K. Lim
AU - B. R. Rosenberg
AU - M. J. Evans
AU - J. R. Johnson
PY - 2026
DA - 2026/09/09
PB - bioRxiv
DO - 10.64898/2026.09.09.749922
UR - https://www.biorxiv.org/content/10.64898/2026.09.09.749922v1
AB - Neurodevelopmental disorders are increasingly associated with immune phenotypes, including autoinflammation, immunodeficiency, and increased susceptibility to severe infection. To determine whether neurodevelopmental disorders-associated genes exert immune functions, we performed an arrayed siRNA screen targeting 28 genes with nonredundant cellular roles and assessed their effects on Zika virus (ZIKV) infection and innate immune pathways. We identified hits that intrinsically restrict ZIKV infection and modulate inflammatory pathways following infection. We further characterized the antiviral activity of the Hao-Fountain syndrome gene USP7, which potently restricts selected neurotropic orthoflaviviruses. USP7 inhibits ZIKV internalization before viral membrane fusion and genome release into the cytoplasm. Because USP7 plays a role in endosomal tubulation and recycling, we investigated whether endosomal recycling pathways restrict ZIKV infection. We identified the USP7-regulated E3 ubiquitin ligase TRIM27, as well as the recycling-associated Rab GTPases RAB11 and RAB35, as potent regulators of ZIKV infection. Infection assays using cell lines expressing pathogenic USP7 variants and primary fibroblasts from individuals with Hao-Fountain syndrome demonstrated that disease-associated USP7 mutations impair its antiviral activity and increase permissivity to ZIKV infection. These findings are consistent with recent case reports of unusually severe viral infection during early life in individuals with Hao-Fountain syndrome. Collectively, our study identifies endosomal recycling pathways as important intrinsic restriction mechanisms against neurotropic orthoflaviviruses and nominates pathogenic USP7 variation as a candidate inborn error of immunity.
ER -