2. Academic Validation
  3. Human-specific activation of the DUX4-SLC34A2 axis by herpesviruses suppresses antiviral innate immunity

Human-specific activation of the DUX4-SLC34A2 axis by herpesviruses suppresses antiviral innate immunity

  • mBio. 2025 Dec 10;16(12):e0255425. doi: 10.1128/mbio.02554-25.
Ming Gao 1 2 3,  Xi Cheng 1 2,  Chuchu Zhang 1 2,  Jiali Ma 1 2,  Xuezhang Tian 1 2,  Shaowei Wang 1 2,  Xiaoyu Xie 4 5,  Yunhong Zhong 1 2,  Siyuan Wang 1 2,  Pinghui Feng 6,  Junjie Zhang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
  • 3 Hubei Key Laboratory of Tumor Biological Behavior, Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 Department of Colorectal and Anal Surgery, Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 5 Hubei Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 6 Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
PMID: 41211819 DOI: 10.1128/mbio.02554-25
Abstract

Viral pathogens employ diverse strategies to antagonize host Antiviral innate immune defenses. However, the human-specific nature of viral immune evasion mechanisms remains poorly understood. Here, we report that herpesvirus Infection selectively activates the embryonic transcription factor DUX4 in human but not murine cells. DUX4 drives the expression of the phosphate transporter SLC34A2, which plays a critical role in suppressing Antiviral innate immunity. Mechanistically, SLC34A2 increases intracellular phosphate levels, thereby suppressing the activity of multiple immune and stress-related kinases, including TBK1. Genetic disruption of DUX4 or SLC34A2 restores innate immune activation and enhances interferon responses. Our findings reveal a previously unrecognized, phosphate-mediated immunosuppressive mechanism and define a human-specific transcriptional circuit exploited by herpesviruses to antagonize innate immunity.IMPORTANCEHerpesviruses are notorious for their ability to evade host immune responses, yet the mechanisms underlying human-specific immune evasion remain poorly understood. This study identifies a previously unrecognized viral immune evasion strategy by which herpesviruses suppress Antiviral immunity in human cells but not murine cells. We demonstrate that herpesvirus Infection induces the expression of the embryonic transcription factor DUX4, which subsequently activates its downstream target, SLC34A2, a phosphate transporter. DUX4-SLC34A2 activation reprograms infected cells toward an embryonic-like transcriptional profile, creating an environment conducive to viral replication. Importantly, we show that SLC34A2 increases intracellular phosphate levels, thereby suppressing the activity of multiple immune and stress-related kinases, including TBK1. Our findings reveal a previously unrecognized phosphate-mediated regulation of Antiviral immunity, providing insights into viral-host interactions and highlighting therapeutic targets for enhancing Antiviral defense.

Keywords

antiviral innate immunity; herpesvirus; immune evasion; phosphate.

Figures
Products