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Updated: May 15, 2026

Cell-Based Drug Screening for Inhibitors of Autophagy Related 4B Cysteine Peptidase
Published on: June 30, 2023
TBK1 restricts IRGQ-mediated autophagy
Uxia Gestal-Mato1, Pauline Lascaux1, Sergio Alejandro Poveda-Cuevas1,2
1Institute of Biochemistry II, Medical Faculty, Goethe University Frankfurt, Frankfurt am Main, Germany.
Abstract:
The autophagy-lysosome system directs the degradation of a wide variety of cytoplasmic cargo such as damaged organelles, protein aggregates, and invading pathogens. The autophagy receptor IRGQ harbors two distinct LIR domains, with LIR1 exhibiting high selectivity for GABARAPL2. Proteomic, biochemical, and high-throughput microscopy studies reveal that the IRGQ-GABARAPL2 complex functions as a hub for the interaction between hATG8s and the autophagy initiation machinery, promoting their lipidation and overall autophagic flux. The interaction of IRGQ with GABARAPL2 is regulated via TBK1. Upon TBK1 activation, GABARAPL2 is phosphorylated on S10, which disrupts IRGQ-GABARAPL2 complexation and therefore its interaction with the autophagy initiation machinery, resulting in a reduction of the autophagic flux of GABARAPL2 and IRGQ-cargo, without affecting bulk autophagy. These findings broaden IRGQ's role in autophagy, identifying it as an interaction hub for autophagy initiation that is negatively regulated by TBK1.
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