Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Dec 5;76(5):797-810.e10.
doi: 10.1016/j.molcel.2019.09.009. Epub 2019 Oct 9.

AUTACs: Cargo-Specific Degraders Using Selective Autophagy

Daiki Takahashi  1 , Jun Moriyama  1 , Tomoe Nakamura  1 , Erika Miki  1 , Eriko Takahashi  1 , Ayami Sato  1 , Takaaki Akaike  2 , Kaori Itto-Nakama  1 , Hirokazu Arimoto  3
Affiliations
Free article

AUTACs: Cargo-Specific Degraders Using Selective Autophagy

Daiki Takahashi et al. Mol Cell. .
Free article

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.

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

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types