STING- induced noncanonical autophagy regulates endolysosomal homeostasis

• 成果类型: Article
• 署名作者: Huang, Tuozhi; Sun, Chenglong; Du, Fenghe; Chen, Zhijian J.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14573
• DOI: 10.1073/pnas.2415422122
• 发表日期: 2025-02-25
• 关键词: cyclic gmp-amp; v-atpase; gene; activation; network; protein; mutations; mechanism; adapter; mtor

摘要

The cGAS-STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well- established role in inducing inflammatory cytokines, activation of the cGAS-STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING- induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced formation of pH- elevated Golgi- derived vesicles that led to ATG16L1 and V- ATPase- dependent noncanonical autophagy. We showed that STING- induced non- canonical autophagy resulted in activation of the MiT/TFE family of transcription factors (TFEB, TFE3, and MITF), which regulate lysosome biogenesis. We found that lipidation of the ATG8 proteins, particularly GABARAPs, inhibited phosphorylation of MiT/TFE transcription factors by mTORC1. The lipidated GABARAPs bound to the Folliculin- interacting proteins (FNIPs), thereby sequestering the FNIP- folliculin protein complexes from activating mTORC1, resulting in dephosphorylation and nuclear translocation of MiT/TFE transcription factors. Furthermore, we found that STING- induced autophagy activated Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson's disease, through GABARAPs lipidation. We further showed that STING- induced autophagy induced ALIX- mediated ESCRT machinery recruitment to mitigate endolysosomal perturbation. These results reveal the multifaceted functions of STING- induced noncanonical autophagy in regulating endolysosomal homeostasis.