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In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
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Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria

Ligang Mei1, Xiaorong Chen1, Fujing Wei1

  • 1School of Life Sciences, Chongqing University, Chongqing, China.

Autophagy
|July 10, 2023
PubMed

Insights

This study introduces a novel autophagy-targeting degradation strategy for large cellular targets like protein aggregates and mitochondria. This approach effectively degrades these targets, offering a new therapeutic avenue for neurodegenerative diseases and cancers.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Drug Discovery

Background:

  • Accumulation of aggregation-prone proteins and malfunctioning organelles is linked to neurodegenerative disorders and cancers.
  • Proteolysis-targeting chimeras (PROTACs) are limited in degrading large targets due to proteasome size constraints.
  • Macroautophagy (autophagy) degrades bulk cytoplasmic components and specific cargoes via autophagosomes.

Purpose of the Study:

  • To develop a generalizable strategy for the targeted degradation of large cellular targets using autophagy.
  • To investigate the efficacy of tethering large targets to autophagy-related proteins ATG16L1 or LC3.
  • To apply this strategy for degrading pathogenic huntingtin (HTT) aggregates and dysfunctional mitochondria.

Main Methods:

  • Tethering large target models to phagophore-associated ATG16L1 or LC3.
  • Utilizing chimeras with polyQ-binding peptide 1 (QBP) and ATG16L1-binding peptide (ABP) or LC3-interacting region (LIR) for HTT aggregate degradation.
  • Employing chimeras with mitochondria-targeting sequences (MTS) and ABP or LIR for mitochondrial degradation.

Main Results:

  • Tethering induced targeted autophagic degradation of large target models.
  • Chimeras successfully degraded pathogenic HTT65Q aggregates.
  • Mitochondria-targeting chimeras degraded dysfunctional mitochondria, ameliorated mitochondrial dysfunction in a Parkinson disease model, and protected against FCCP-induced apoptosis.

Conclusions:

  • A novel, generalizable autophagy-targeting degradation strategy for large targets has been developed.
  • This strategy effectively degrades pathogenic protein aggregates and dysfunctional mitochondria.
  • The approach expands the toolkit for targeted protein degradation and offers potential therapeutic applications.
Keywords:
ATG16L1HTT65Q aggregatesLC3autophagy-targeting degradationmitochondriaproteolysis-targeting chimeras

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