STING activation drives pericentrosomal positioning of acidic organelles via the VAIL-LRRK2-Rab35 pathway
- 1The University of Tokyo
Abstract
The cGAS-STING pathway is an innate immune system that responds to cytoplasmic double-stranded DNA, but recent studies have highlighted its noncanonical role in facilitating lysosomal stress responses. Specifically, STING activation has been shown to trigger V-ATPase-ATG16L1-induced LC3 lipidation (VAIL) and to activate LRRK2, a Parkinson disease-associated kinase, but the detailed molecular mechanism and the physiological roles of the activation have remained unclear. Here, we found that STING activation in microglia induces the translocation of LRRK2 to the pericentrosomal area, where lysosomes and recycling endosomes (REs) concentrate. This process was VAIL-dependent, and LRRK2 was found to be localized to the organelles. The translocation of LRRK2 required intact microtubule structures and was mediated by LRRK2 kinase activity, its substrate Rab35 and the motor adaptor proteins including JIP4. All these proteins were concentrated at the pericentrosomal area upon STING stimulation. The hyperactivating G2019S mutation of LRRK2 promoted the pericentrosomal translocation of these proteins. Overall, we propose a novel STING-induced noncanonical pathway that involves LRRK2 to facilitate pericentrosomal organelle positioning.
Related
- SMIM1 drives an alternative iron uptake pathway
- SPHK1 drives pyroptosis via ROS-dependent activation of the NLRP3 inflammasome in non-infectious uveitis
- Carbon-Ion-Induced Activation of the NF-κB Pathway
- Pregnancy Impacts Maternal Sleep: Focus on Kynurenine Pathway Activation in Female Rats
- Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype
BibTeX
@misc{suenaga2026sting,
title = {{STING activation drives pericentrosomal positioning of acidic organelles via the VAIL-LRRK2-Rab35 pathway}},
author = {S. Suenaga and M. Sakurai and T. Iwatsubo and T. Kuwahara},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.750829},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.750829v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - STING activation drives pericentrosomal positioning of acidic organelles via the VAIL-LRRK2-Rab35 pathway
AU - S. Suenaga
AU - M. Sakurai
AU - T. Iwatsubo
AU - T. Kuwahara
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.750829
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.750829v1
AB - The cGAS-STING pathway is an innate immune system that responds to cytoplasmic double-stranded DNA, but recent studies have highlighted its noncanonical role in facilitating lysosomal stress responses. Specifically, STING activation has been shown to trigger V-ATPase-ATG16L1-induced LC3 lipidation (VAIL) and to activate LRRK2, a Parkinson disease-associated kinase, but the detailed molecular mechanism and the physiological roles of the activation have remained unclear. Here, we found that STING activation in microglia induces the translocation of LRRK2 to the pericentrosomal area, where lysosomes and recycling endosomes (REs) concentrate. This process was VAIL-dependent, and LRRK2 was found to be localized to the organelles. The translocation of LRRK2 required intact microtubule structures and was mediated by LRRK2 kinase activity, its substrate Rab35 and the motor adaptor proteins including JIP4. All these proteins were concentrated at the pericentrosomal area upon STING stimulation. The hyperactivating G2019S mutation of LRRK2 promoted the pericentrosomal translocation of these proteins. Overall, we propose a novel STING-induced noncanonical pathway that involves LRRK2 to facilitate pericentrosomal organelle positioning.
ER -