AUTAC4 is a Mitochondria-targeting Autophagy-targeting Chimera (AUTAC). Besides, AUTAC4 downregulates cytosolic proteins and promotes targeted mitochondrial turnover via mitophagy.
Autophagy-targeting chimera (AUTAC) degrades target proteins via a lysosomal pathway rather than the common proteasome pathway. Besides, One end of AUTAC is a target protein-ligand, the other end is a site of K63 ubiquitin modification, and the two parts are connected by a linker. Moreover, AUTAC induces recognition of LC3 receptors of autophagosomes by K63-linked polyubiquitination. Additionally, the Target-AUTAC complex was phagocytosed and transferred into lysosomal for degradation.
Mitophagy is the selective degradation of mitochondria by autophagy. Besides, Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. Furthermore, Autophagy and mitophagy are important cellular processes that are responsible for breaking down cellular contents, preserving energy and safeguarding against the accumulation of damaged and aggregated biomolecules.
AUTAC4 rescues cells with acute mitochondrial injury by promoting mitophagy.
AUTAC4 can deliver a guanine tag onto the mitochondrial membrane. Besides, AUTAC4 induces K63-linked polyubiquitination and accumulation of K63-linked polyubiquitin required approximately 8 h of incubation. What’s more, AUTAC4 suppresses not only cytochrome c release into the cytosol but also pro-caspase 3 cleavage. Moreover, The intracellular ATP level after CCCP treatment is also maintained by AUTAC4, suggesting that mitophagy acceleration by AUTAC4 restored energy production by improving mitochondrial quality control. Additionally, AUTAC4 (40 Μm; 10h) induces degradation and biogenesis of mitochondria in HeLa cells.
AUTAC4 (10 μM) can induce mitophagy in Detroit 532 cells ~24-72 h after treatment With the use of mito-Rosella. Besides, AUTAC4 (10 μM, 3 days) improves the mitochondrial morphology and mitochondrial membrane potential in Detroit 532 cells.
In conclusion, AUTAC4 is a Mitochondria-targeting Autophagy-targeting Chimera. Besides, AUTAC4 induces K63-linked polyubiquitination. Furthermore, AUTAC4 rescues cells with acute mitochondrial injury by promoting mitophagy.
Reference
[1] Takahashi D, et al.Autophagy. 2020 Apr;16(4):765-766.
[2] Takahashi D, et al. Mol Cell. 2019 Dec 5;76(5):797-810.e10.