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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.
Nature Communications
|May 13, 2026
Summary
The autophagy receptor IRGQ, interacting with GABARAPL2, acts as a hub for autophagy initiation. TBK1 activation disrupts this complex, reducing specific autophagic flux without impacting bulk autophagy.
Area of Science:
- Cellular Biology
- Molecular Biology
- Autophagy Research
Background:
- The autophagy-lysosome system is crucial for degrading cellular components like damaged organelles and pathogens.
- Autophagy receptors, such as IRGQ, play key roles in cargo recognition and delivery for degradation.
- The hATG8 family proteins are essential mediators in the autophagy pathway.
Purpose of the Study:
- To investigate the role of the autophagy receptor IRGQ and its interaction with GABARAPL2 in regulating autophagic flux.
- To elucidate the mechanism by which TBK1 regulates the IRGQ-GABARAPL2 complex.
- To understand how this regulation impacts the initiation of autophagy and cargo-specific degradation.
Main Methods:
- Proteomic analysis to identify protein interactions.
- Biochemical assays to confirm binding affinities and regulatory mechanisms.
- High-throughput microscopy to visualize and quantify autophagic processes in live cells.
Main Results:
- The IRGQ-GABARAPL2 complex serves as a critical interaction hub between hATG8s and autophagy initiation factors, promoting lipidation and autophagic flux.
- TBK1 activation leads to GABARAPL2 phosphorylation at S10, disrupting the IRGQ-GABARAPL2 complex.
- This disruption reduces the autophagic flux of GABARAPL2 and IRGQ-bound cargo, while bulk autophagy remains unaffected.
Conclusions:
- IRQG functions as a regulated interaction hub for autophagy initiation.
- TBK1 negatively regulates this hub through phosphorylation of GABARAPL2, thereby controlling specific autophagic pathways.
- These findings expand the understanding of IRGQ's function and the intricate regulation of selective autophagy.
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