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  3. NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking

NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking

  • Cell Rep. 2023 Feb 28;42(3):112185. doi: 10.1016/j.celrep.2023.112185.
Lulu Zhang 1,  Xubiao Wei 1,  Zhimeng Wang 1,  Peiyuan Liu 2,  Yanfei Hou 3,  Yifang Xu 3,  Huili Su 3,  Matthew D Koci 4,  Hang Yin 5,  Conggang Zhang 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
  • 2 School of Life Science, Tianjin University, Tianjin, China.
  • 3 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Prestage Department of Poultry Science, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, USA.
  • 5 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China. Electronic address: yin_hang@tsinghua.edu.cn.
  • 6 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China. Electronic address: cgzhang@tsinghua.edu.cn.
PMID: 36857187 DOI: 10.1016/j.celrep.2023.112185
Abstract

It is widely known that stimulator of interferon genes (STING) can trigger nuclear factor κB (NF-κB) signaling. However, whether and how the NF-κB pathway affects STING signaling remains largely unclear. Here, we report that Toll-like Receptor (TLR)-, interleukin-1 receptor (IL-1R)-, tumor necrosis factor receptor (TNFR)-, growth factor receptor (GF-R)-, and protein kinase C (PKC)-mediated NF-κB signaling activation dramatically enhances STING-mediated immune responses. Mechanistically, we find that STING interacts with microtubules, which plays a crucial role in STING intracellular trafficking. We further uncover that activation of the canonical NF-κB pathway induces microtubule depolymerization, which inhibits STING trafficking to lysosomes for degradation. This leads to increased levels of activated STING that persist for a longer period of time. The synergy between NF-κB and STING triggers a cascade-amplified interferon response and robust host Antiviral defense. In addition, we observe that several gain-of-function mutations of STING abolish the microtubule-STING interaction and cause abnormal STING trafficking and ligand-independent STING autoactivation. Collectively, our data demonstrate that NF-κB activation enhances STING signaling by regulating microtubule-mediated STING trafficking.

Keywords

CP: Immunology; NF-κB signaling pathways; SAVI; STING degradation; Toll-like receptors; innate immunity; microtubule depolymerization.

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