Authors
Xianteng Hou, Qing Wu, Yangting Du, Changwan Wang, Junyan Zhu, Yingbo Jiang, She Chen, Lisha Zhou, Xiaoyu Wu, Hongyan Wang, Hui Yang, Fajian Hou
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 38. Pages e2608171123. Sep 22, 2026. Epub Sep 15, 2026.
Abstract
The cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is essential for antiviral immunity, and its dysregulation causes inflammatory disease. The mechanism underlying STING activation, including its essential endoplasmic reticulum-to-Golgi translocation, has remained elusive. Here, we identify a dedicated actin-based transport system licensed by the smooth muscle actin isoform ACTA2 via in vitro reconstitution. Superresolution live imaging reveals STING becomes punctate and activated while moving along ACTA2 filaments. This ACTA2-directed network is required for antiviral interferon responses against HSV-1. Strikingly, it also drives pathological interferon production and lethal autoimmunity in Trex1-/- mice, where its genetic or pharmacological disruption rescues disease. Furthermore, ACTA2 expression correlates with proinflammatory cytokine levels in peripheral blood mononuclear cells from systemic lupus erythematosus patients, and its downregulation ameliorates this inflammatory signature. Our work defines a specific cytoskeletal network that governs STING-dependent inflammatory responses to both foreign and self-DNA, thereby establishing stimulus-directed organelle trafficking as a central control point in innate immune signaling.
PMID:
42743285
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.
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