FXR2 Promotes Autophagic Clearance of Sindbis Virus Capsid and Protects Against Viral Encephalitis
- 1University of Texas Southwestern Medical Center
Abstract
Autophagy protects neurons from viral infection by removing toxic viral components, but the host factors that recognize viral proteins and direct their clearance remain incompletely defined. Here, we identify fragile X mental retardation syndrome-related protein 2 (FXR2) as a mediator of protective autophagy during Sindbis virus (SINV) infection. Quantitative proteomic analysis of host proteins associated with SINV capsid identified FXR2, an RNA-binding protein linked to stress granules and protein homeostasis. Co-immunoprecipitation and immunofluorescence confirmed that FXR2 associates and colocalizes with viral capsid in infected cells. Loss of FXR2 increased capsid accumulation, reduced LC3 lipidation and autophagosome formation, and impaired p62 degradation following infection. Reconstitution of FXR2-deficient cells restored autophagy and promoted capsid clearance. Although FXR2 deficiency did not significantly increase viral replication, it enhanced virus-induced cell death, suggesting that FXR2 protects infected cells by limiting viral protein toxicity rather than by directly restricting virus production. Consistent with this model, both Fxr2-null and heterozygous mice exhibited increased mortality following neurotropic SINV challenge, and Fxr2-null mice developed greater neuronal degeneration, inflammation, and cell death despite viral titers comparable to those in wild-type animals. Together, these findings identify FXR2 as a previously unrecognized component of the antiviral autophagy pathway that promotes viral capsid clearance and protects neural tissue from infection-associated damage.
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BibTeX
@misc{singh2026fxr2,
title = {{FXR2 Promotes Autophagic Clearance of Sindbis Virus Capsid and Protects Against Viral Encephalitis}},
author = {V. Singh and P. W. Dryden and W. Y. Chang and Z. Zou and Y. Gu and D. L. Nelson and T. Wang and J. W. Thinwa and T. A. Reese},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.761393},
url = {https://www.biorxiv.org/content/10.64898/2026.10.23.761393v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - FXR2 Promotes Autophagic Clearance of Sindbis Virus Capsid and Protects Against Viral Encephalitis
AU - V. Singh
AU - P. W. Dryden
AU - W. Y. Chang
AU - Z. Zou
AU - Y. Gu
AU - D. L. Nelson
AU - T. Wang
AU - J. W. Thinwa
AU - T. A. Reese
PY - 2026
DA - 2026/10/23
PB - bioRxiv
DO - 10.64898/2026.10.23.761393
UR - https://www.biorxiv.org/content/10.64898/2026.10.23.761393v1
AB - Autophagy protects neurons from viral infection by removing toxic viral components, but the host factors that recognize viral proteins and direct their clearance remain incompletely defined. Here, we identify fragile X mental retardation syndrome-related protein 2 (FXR2) as a mediator of protective autophagy during Sindbis virus (SINV) infection. Quantitative proteomic analysis of host proteins associated with SINV capsid identified FXR2, an RNA-binding protein linked to stress granules and protein homeostasis. Co-immunoprecipitation and immunofluorescence confirmed that FXR2 associates and colocalizes with viral capsid in infected cells. Loss of FXR2 increased capsid accumulation, reduced LC3 lipidation and autophagosome formation, and impaired p62 degradation following infection. Reconstitution of FXR2-deficient cells restored autophagy and promoted capsid clearance. Although FXR2 deficiency did not significantly increase viral replication, it enhanced virus-induced cell death, suggesting that FXR2 protects infected cells by limiting viral protein toxicity rather than by directly restricting virus production. Consistent with this model, both Fxr2-null and heterozygous mice exhibited increased mortality following neurotropic SINV challenge, and Fxr2-null mice developed greater neuronal degeneration, inflammation, and cell death despite viral titers comparable to those in wild-type animals. Together, these findings identify FXR2 as a previously unrecognized component of the antiviral autophagy pathway that promotes viral capsid clearance and protects neural tissue from infection-associated damage.
ER -