1. Academic Validation
  2. STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy

STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy

  • Cell Insight. 2024 Feb 2;3(2):100147. doi: 10.1016/j.cellin.2024.100147.
Xiaoyu Song 1 2 Yufeng Xi 3 Ming Dai 1 2 Tao Li 1 4 Shihao Du 1 4 Yuxin Zhu 1 2 Mengjie Li 1 2 Yunze Li 1 2 Siqi Liu 5 Xia Ding 1 4 Xuebiao Yao 1 2 Ying Lai 3 Xing Liu 1 2
Affiliations

Affiliations

  • 1 MOE Key Laboratory for Cellular Dynamics, University of Science & Technology of China School of Life Sciences, Hefei, China.
  • 2 Anhui Key Laboratory for Chemical Biology & Hefei National Center for Cross-disciplinary Sciences, Hefei, China.
  • 3 National Clinical Research Center for Geriatrics, West China Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.
  • 4 Department of Gastroenterology, Beijing University of Chinese Medicine, Beijing, China.
  • 5 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.
Abstract

The stimulator of interferon genes (STING) plays a pivotal role in orchestrating innate immunity, and dysregulated activity of STING has been implicated in the pathogenesis of autoimmune diseases. Recent findings suggest that Bacterial infection activates STING, relieving ER stress, and triggers non-canonical Autophagy by spatially regulating STX17. Despite these insights, the precise mechanism governing the dynamics of autophagosome fusion elicited by STING remains unclear. In this study, we demonstrate that dynamic STING activation guides the Autophagy flux, mirroring the trajectory of canonical Autophagy adaptors. STING engages in a physical interaction with STX17, and agonist-induced phosphorylation or degradation alleviates STING's inhibitory effects on the assembly of the STX17-SNAP29-VAMP8 complex. Consistent with these findings, degradation-deficient mutants hinder Autophagy flux by impeding STX17-mediated autophagosome-lysosome fusion. Moreover, STING mutants associated with lupus disrupt the assembly of the STX17-SNAP29-VAMP8 complex and Autophagy process, which lead to persistent STING activation and elevated IFN-β production. Our results highlight that the intracellular trajectory of STING, coupled with Autophagy flux, guides the assembly and membrane fusion of the STX17-SNAP29-VAMP8 complex, ensuring the accurate regulation of innate immunity.

Keywords

Autophagy; Innate immunity; Phosphorylation; STING; STX17.

Figures
Products