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

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112185
• Main Authors: Zhang, Lulu, Wei, Xubiao, Wang, Zhimeng, Liu, Peiyuan, Hou, Yanfei, Xu, Yifang, Su, Huili, Koci, Matthew D., Yin, Hang, Zhang, Conggang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: CP: Immunology; innate immunity; Interferons; Membrane Proteins; microtubule depolymerization; NF-kappa B - metabolism; NF-κB signaling pathways; SAVI; Signal Transduction - genetics; STING degradation; Toll-Like Receptors; CP: Immunology; microtubule depolymerization; innate immunity; SAVI; Toll-like receptors; STING degradation; NF-κB signaling pathways
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112185

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. [Display omitted] •Activation of a wide range of NF-κB pathways enhances STING signaling responses•NF-κB activation prevents STING degradation and thus enhances STING signaling•NF-κB activation blocks STING turnoff by altering microtubule-based STING transport•Damaged STING-microtubule interaction induces STING hyperactivation Zhang et al. find that activation of a wide range of NF-κB pathways enhances STING-mediated immune responses. NF-κB activation blocks STING degradation by inhibiting microtubule-mediated STING trafficking from the Golgi apparatus to lysosomes and thus prolongs and increases STING signaling. This then augments STING-mediated interferon responses and host antiviral defenses.