Abstract
Toll-like receptors (TLRs) are central to host defense and tissue repair, yet dysregulated TLR signaling contributes to inflammatory and autoimmune diseases. Although core TLR pathways have been defined, the mechanisms that terminate receptor signaling and restore immune homeostasis remain incompletely understood. Here, we identify the zinc finger protein Zfand5, a known proteasomal shuttling factor, as a selective negative regulator of TLR3- and TLR4-mediated inflammatory responses. Zfand5-deficient mice exhibit exacerbated sepsis and heightened cytokine production following TLR3/4 stimulation. Mechanistically, Zfand5 facilitates the proteasomal degradation of the adaptor protein TIR-domain-containing adapter-inducing interferon-β (TRIF) by bridging polyubiquitinated TRIF to the proteasome, thereby terminating downstream pro-inflammatory and type I interferon signaling. Loss of Zfand5 also enhances TRIF-dependent necroptosis upon TLR3/4 activation, further amplifying inflammation. These findings reveal an essential and previously unrecognized role for Zfand5 in regulating TRIF turnover and maintaining immune balance during innate immune responses.
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Acknowledgements
We thank Drs. Ken Watanabe and Chien-Kuo Lee for the generous gifts of plasmids and cells; the Transgenic Mouse Model Core Facility of the National Core Facility Program for Biotechnology; the Ministry of Science and Technology, Taiwan; and the Gene Knockout Mouse Core Laboratory of the National Taiwan University Center of Genomic Medicine for providing technical services. We are grateful to the staff of the Second Core Lab, Department of Medical Research, National Taiwan University Hospital, for their technical support. We also acknowledge Dr. Pei-Lin Cheng at the Institute of Molecular Biology, Academia Sinica, for support with proteasome isolation, as well as the 3rd Core Facility and the Microscopy Core Facility of the Department of Medical Research at National Taiwan University Hospital for technical support throughout this study.
Funding
This work was supported by the Ministry of Education in Taiwan, National Taiwan University (NTU-CC-114L894103 to L-CH, and 112-L2001 and 114-L1001 to C-YL), the National Science and Technology Council (NSTC) of Taiwan (111-2320-B-002-048-MY3, and 113-2326-B-002-011 to L-CH, and 112-2314-B-002-141, 112-2326-B-002-005, 113-2326-B-002-013, and 113-2314-B-002-244 to C-YL), the National Health Research Institutes, Taiwan (NHRI-EX113-11334SI to L-CH), and the Academia Sinica (AS) Thematic Program (AS-TP-114-L02 to L-CH).
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Liao, WT., Shen, CH., Winarso, V.A. et al. Zfand5 terminates TLR3/4 signaling and necroptosis by targeting TRIF to the proteasome for degradation. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08946-0
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DOI: https://doi.org/10.1038/s41419-026-08946-0
