Journal
EMBO JOURNAL
Volume 42, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/embj.2022112387
Keywords
autophagy; cGAS; cytoplasmic DNA; STING; WIPI2
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The cGAS-STING pathway plays a crucial role in host defense by sensing pathogen DNA and inducing immune responses. In this study, it was discovered that STING directly interacts with WIPI2, a key protein involved in autophagy. This interaction is necessary for the formation of autophagosomes induced by STING, but does not affect the activation and trafficking of STING. Furthermore, the specific interaction between STING and WIPI2 leads to competition with PI3P binding, resulting in mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy.
The cGAS-STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS-STING pathway-induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING-induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P-binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. Furthermore, we show that the STING-WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS-STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation.
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