MINDing the brain: IRGQ as a molecular switch between degradative and secretory autophagy in membrane quality control and neuroinflammation

Objective

Neurodegenerative diseases and chronic brain inflammation affect millions and still lack effective, mechanism-based treatments. Failures in cellular quality control such as autophagy fuel neuro-inflammation and neuro-degeneration. Our recent work (Herhaus, Cell 2024) identified IRGQ as a new autophagy receptor which directs cargo either to lysosomal degradation (degradative autophagy) or to membrane presentation and cell release (secretory autophagy). IRGQ is essential in maintaining membrane integrity and limiting inflammatory signalling. Our new preliminary data show that IRGQ loss alters immune-synapse readouts and reveal IRGQ as a scaffold for the autophagy initiation machinery and vesicle trafficking regulators—clear motivation to probe brain inflammation and early neurodegeneration in vivo. Our proposal, MIND (Membrane quality control and IRGQ in Neurodegeneration) combines strong molecular biology with in vivo disease relevance. Building on recent structural and functional evidence that IRGQ binds core autophagy proteins and controls immune cargo, we will: (1) define, with precision, how IRGQ engages the autophagy machinery to route cargo; (2) map how stress reshapes this routing and defines inflammatory signalling; and (3) test consequences in the brain across the lifespan. We bring unique resources. A novel, unpublished, viable full-body IRGQ knockout mouse, with aged cohorts already available; and advanced molecular expertise in autophagy combined with cutting-edge imaging and proteomics platforms to conduct cell-based screens, and multi-omics and histopathology of our mouse model. Within 24 months, we aim to characterise IRGQ as a molecular switch that coordinates degradative and secretory autophagy to safeguard cellular integrity and restrains neuroinflammation. The expected outcomes include mechanistic insights into vesicle fate decisions, disease-relevant in vivo data, and the establishment of IRGQ as a new target for modulating neuroinflammation.