STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy.

Abstract

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.

• Authors: Wei Wan, Chuying Qian, Qian Wang, Jin Li, Hongtao Zhang, Lei Wang, Maomao Pu, Yewei Huang, Zhengfu He, Tianhua Zhou, Han-Ming Shen, Wei Liu
• Journal: The EMBO journal (EMBO J) Vol. 42 Issue 8 Pg. e112387 (04 17 2023) ISSN: 1460-2075 [Electronic] England
• PMID: 36872914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors.

Chemical References

• DNA
• Membrane Proteins
• Nucleotidyltransferases
• STING1 protein, human
• WIPI2 protein, human

Topics

• Autophagosomes (metabolism)
• Autophagy (physiology)
• DNA (metabolism)
• Membrane Proteins (genetics, metabolism)
• Nucleotidyltransferases (metabolism)
• Humans