A STING-CASM-GABARAP pathway activates LRRK2 at lysosomes.

Area of Science:

• Cellular Biology
• Molecular Mechanisms
• Disease Pathogenesis

Background:

• Mutations in LRRK2 kinase are associated with Parkinson's and Crohn's diseases.
• LRRK2 kinase activity is known to increase upon lysosome damage.
• Endogenous cellular mechanisms regulating LRRK2 kinase activity remain largely uncharacterized.

Purpose of the Study:

• To elucidate the endogenous cellular mechanisms controlling LRRK2 kinase activity.
• To identify novel pathways that activate LRRK2.
• To understand the role of lysosomal homeostasis in LRRK2 regulation.

Main Methods:

• Investigated the role of stimulator of interferon genes (STING) signaling in LRRK2 activation.
• Utilized the conjugation of ATG8 to single membranes (CASM) pathway as a focus.
• Examined the impact of chemical stimuli perturbing lysosomal homeostasis on LRRK2.
• Analyzed the specific contribution of GABARAP proteins to LRRK2 lysosome recruitment and activation.

Main Results:

• Identified STING signaling as an activator of LRRK2 through the CASM pathway.
• Demonstrated that various stimuli disrupting lysosomal homeostasis converge on CASM to activate LRRK2.
• Established that LRRK2 activation and lysosome recruitment are critically dependent on interactions with the GABARAP protein family.
• Showcased that CASM pathway activation leads to lipidation of multiple ATG8 protein family members.

Conclusions:

• Defined a novel pathway integrating lysosomal stimuli to control LRRK2 kinase activity.
• The identified pathway provides a mechanistic link between lysosomal dysfunction and LRRK2 activation.
• Aberrant activation of LRRK2 through this pathway may contribute to the pathogenesis of Parkinson's and Crohn's diseases.