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

It is widely known that stimulator of interferon genes (STING) can trigger nuclear factor KB (NF-KB) signaling. However, whether and how the NF-KB 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-KB signaling activation dramatically enhances STING-mediated immune responses. Mechanistically, we find that STING interacts with microtu-bules, which plays a crucial role in STING intracellular trafficking. We further uncover that activation of the canonical NF-KB pathway induces microtubule depolymerization, which inhibits STING trafficking to lyso-somes for degradation. This leads to increased levels of activated STING that persist for a longer period of time. The synergy between NF-KB 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-KB activation enhances STING signaling by regu-lating microtubule-mediated STING trafficking.

Automated summary

NF-KB pathway activation enhances STING signaling by regulating microtubule-mediated STING trafficking, leading to robust host antiviral defense and amplified interferon response.