SARS-CoV-2 ORF6 protein targets IFP35 to inhibit the IFNγ signaling pathway.
- 1Guangzhou National Laboratory Guangzhou China.
- 2Centre for Infection and Immunity Studies (CIIS), School of Medicine Shenzhen Campus of Sun Yat-sen University Shenzhen China.
- 3Guizhou University of Traditional Chinese Medicine Guiyang China.
Abstract
The innate immune system functions as the frontline barrier against invading pathogens, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nevertheless, the virus has developed various strategies to effectively regulate host immune responses, particularly through the inhibition of interferon signaling. In this study, we identify the SARS-CoV-2 accessory protein ORF6 as a key inhibitor of interferon gamma (IFNγ) signaling through downregulation of the interferon-induced 35-kDa protein (IFP35). IFP35, an interferon-stimulated gene (ISG) critical for interferon -mediated antiviral response, is significantly upregulated during SARS-CoV-2 infection. Silencing IFP35 via RNA interference enhances viral replication, indicating its antiviral role. Furthermore, we demonstrate that ORF6 associates with IFP35 and accelerates its ubiquitin-proteasome degradation, thereby impairing IFP35's ability to activate IFNγ signaling. These data reveal novel mechanisms used by SARS-CoV-2 to circumvent host immunity, specifically by impairing IFNγ signaling.
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BibTeX
@article{liu2026sarscov2,
title = {{SARS-CoV-2 ORF6 protein targets IFP35 to inhibit the IFNγ signaling pathway.}},
author = {Lihong Liu and Jie Du and Jiacheng Huang and Sidi Yang and Qiaoqiao Xiao and Liu Cao and Hong Peng and Birong Zheng and Chunmei Li and Deyin Guo},
journal = {MLife},
year = {2026},
month = oct,
doi = {10.1002/mlf2.70112},
url = {https://europepmc.org/article/MED/42948185},
note = {CC BY},
}
RIS
TY - JOUR
TI - SARS-CoV-2 ORF6 protein targets IFP35 to inhibit the IFNγ signaling pathway.
AU - Lihong Liu
AU - Jie Du
AU - Jiacheng Huang
AU - Sidi Yang
AU - Qiaoqiao Xiao
AU - Liu Cao
AU - Hong Peng
AU - Birong Zheng
AU - Chunmei Li
AU - Deyin Guo
PY - 2026
DA - 2026/10/26
JO - MLife
DO - 10.1002/mlf2.70112
UR - https://europepmc.org/article/MED/42948185
AB - The innate immune system functions as the frontline barrier against invading pathogens, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nevertheless, the virus has developed various strategies to effectively regulate host immune responses, particularly through the inhibition of interferon signaling. In this study, we identify the SARS-CoV-2 accessory protein ORF6 as a key inhibitor of interferon gamma (IFNγ) signaling through downregulation of the interferon-induced 35-kDa protein (IFP35). IFP35, an interferon-stimulated gene (ISG) critical for interferon -mediated antiviral response, is significantly upregulated during SARS-CoV-2 infection. Silencing IFP35 via RNA interference enhances viral replication, indicating its antiviral role. Furthermore, we demonstrate that ORF6 associates with IFP35 and accelerates its ubiquitin-proteasome degradation, thereby impairing IFP35's ability to activate IFNγ signaling. These data reveal novel mechanisms used by SARS-CoV-2 to circumvent host immunity, specifically by impairing IFNγ signaling.
SN - 2097-1699
SN - 2770-100X
ER -