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Prion-like MAVS fibrils stitch mitochondria to promote a rapid antiviral response

Cellular & Molecular Immunology volume 23, pages 204–219 (2026)Cite this article

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Abstract

Innate immunity in host cells must be rapidly activated to combat invading microbes. Upon RIG-I activation, the transcription of type I interferons is induced within one hour in virus-infected cells. Previous studies have shown that endogenous MAVS spreads signals via aggregation on the mitochondrial membrane, whereas truncated recombinant MAVS forms prion-like filaments in vitro. How MAVS transmits signals so quickly, and the molecular architecture of its membrane aggregates, remains elusive. Here, we report that activated MAVS forms fibrils encircling its resident mitochondrion or connecting neighboring mitochondria with a “ladder-like” structure, allowing the activation of dormant MAVS on encountered mitochondria. This “intermitochondrial activation” process promotes a rapid antiviral response in cells to overcome the immediate danger caused by viruses. Moreover, stuck MAVS fibrils between mitochondria have limited cytosolic protein access and thus relay signals poorly. This study demonstrated that prion-like MAVS fibrils cluster in mitochondria to ensure a rapid antiviral response.

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Fig. 1: Activated MAVS induces mitochondrial clustering in cells.
Fig. 2: Activated MAVS assembles to form fibrils that connect mitochondria within cells.
Fig. 3: Parallel MAVS fibrils surrounding mitochondria in patches.
Fig. 4: MAVS fibrils activate nearby dormant mitochondria to propagate antiviral signals.
Fig. 5: Mitochondrial clustering is mediated by protein aggregation and a linker region without sequence specificity.
Fig. 6: Fibrils stuck in the intermitochondrial region have limited access to cytosolic proteins.
Fig. 7: The balance between exposed and stuck MAVS fibrils influences MAVS activation.

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Acknowledgements

We thank members from the Core Facility at the National Center for Protein Sciences at Peking University for assistance with electron microscopy, optical microscopy, and flow cytometry, particularly Drs. Yiqun Liu and Yingchun Hu, Mses Hongmei Zhang, Pengyuan Dong, Rui Jiao, Mrs. Xinpeng He, Hongzhang Zhou, and Zhenyang Kong for their invaluable technical assistance with electron microscopy; Drs. Jun Ren and Chunyan Shan for their invaluable technical assistance with optical microscopy, and Mrs. Liying Du, Dr. Jia Luo, and Dr. Huan Yang for their invaluable technical assistance with flow cytometry. We thank members from the Laboratory of Electron Microscopy and Cryo-EM Platform of Peking University for assistance with cryo-FIB milling and cryo-ET data collection, particularly Drs. Zhenxi Guo and Changdong Qin, Ms. Xia Pei, and Mr. Bo Shao for device setup. We thank the high-performance computing platform of Peking University for assisting with the computational resources. We thank the Center for Biological Imaging (CBI), Institute of Biophysics, for assisting with cryo-ET data collection. We thank Congyi Zhen for the viruses, Liang Li for the modifications of the calculation-related Python scripts, and Junhan Yang and Shenjia Luo for assisting in image processing.

Funding

This work was supported by the National Natural Science Foundation of China (32130038), the Chinese Ministry of Science and Technology (2024YFA1306501 and 2022YFC2303700), the China Postdoctoral Science Foundation (2021M700242 and 2022T150017), and the Young Elite Scientists Sponsorship Program by CAST (2022QNRC001).

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  1. These authors contributed equally: Xiaoyu Yu, Panpan Wang.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China

    Xiaoyu Yu, Panpan Wang, Nanhai Zhou, Liyuan Zhang, Xiao Gong, Qiang Guo & Zhengfan Jiang

  2. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

    Xiaoyu Yu, Panpan Wang, Nanhai Zhou, Liyuan Zhang, Xiao Gong, Qiang Guo & Zhengfan Jiang

  3. Changping Laboratory, Beijing, China

    Panpan Wang & Qiang Guo

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Contributions

XY, PW, QG, and ZJ designed the research; XY and PW performed the experiments; LZ, NZ, and XG assisted in the experiments; XY, PW, QG, and ZJ analyzed the data and wrote the manuscript.

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Yu, X., Wang, P., Zhou, N. et al. Prion-like MAVS fibrils stitch mitochondria to promote a rapid antiviral response. Cell Mol Immunol 23, 204–219 (2026). https://doi.org/10.1038/s41423-025-01382-8

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