AUTACs: Cargo-Specific Degraders Using Selective Autophagy

Daiki Takahashi, Jun Moriyama, Tomoe Nakamura, Erika Miki, Eriko Takahashi, Ayami Sato, Takaaki Akaike, Kaori Itto-Nakama, Hirokazu Arimoto

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Protein silencing represents an essential tool in biomedical research. Targeted protein degradation (TPD) strategies exemplified by PROTACs are rapidly emerging as modalities in drug discovery. However, the scope of current TPD techniques is limited because many intracellular materials are not substrates of proteasomal clearance. Here, we described a novel targeted-clearance strategy (autophagy-targeting chimera [AUTAC]) that contains a degradation tag (guanine derivatives) and a warhead to provide target specificity. As expected from the substrate scope of autophagy, AUTAC degraded fragmented mitochondria as well as proteins. Mitochondria-targeted AUTAC accelerated both the removal of dysfunctional fragmented mitochondria and the biogenesis of functionally normal mitochondria in patient-derived fibroblast cells. Cytoprotective effects against acute mitochondrial injuries were also seen. Canonical autophagy is viewed as a nonselective bulk decomposition system, and none of the available autophagy-inducing agents exhibit useful cargo selectivity. With its target specificity, AUTAC provides a new modality for research on autophagy-based drugs.

Original languageEnglish
Pages (from-to)797-810.e10
JournalMolecular Cell
Volume76
Issue number5
DOIs
Publication statusPublished - 2019 Dec 5

Keywords

  • AUTAC
  • Down syndrome
  • K63-linked polyubiquitin
  • PROTACs
  • S-guanylation
  • autophagy
  • cargo-specific degrader
  • drug discovery
  • mitophagy
  • targeted protein degradation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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