DNA-PKcs-Driven YAP1 Phosphorylation and Nuclear Translocation: a Key Regulator of Ferroptosis in
Junyan Wang1, Xing Chang2, Chun Li1
1State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Abstract:
The DNA-Dependent Protein Kinase catalytic subunit (DNA-PKcs) acts as a principal executor in the DNA damage response (DDR), mediating the phosphorylation of a broad spectrum of substrates integral to DNA repair and apoptosis. This investigation seeks to discern the possible association and mechanisms linking hyperglycemia-induced ferroptosis and DNA-PKcs in DCM. This data exhibits a substantial activation of DNAPKcs- dependent DDR in mice with streptozotocin-induced DCM. However, deletion of DNA-PKcs in cardiomyocytes notably mitigates DNA damage, enhances heart function and dampens the inflammatory response. Co-IP/MS analysis and subsequent validation experiments demonstrate that DNA-PKcs directly interacts with and phosphorylates YAP1 at Thr226. This phosphorylation event facilitates the nuclear retention of YAP1, where it intensifies the transcription of ferroptosis-associated genes. Knockin mice expressing a nonphosphorylatable T226A YAP1 mutant display decreased ferroptosis, reduced myocardial fibrosis and improved heart function. Taken together, this study unravels that DDR acts as an intracellular stress damage sensor, perceiving hyperglycemic conditions and subsequently transmitting the damage signal to incite ferroptosis through the interplay between DNA-PKcs and YAP1. This novel insight suggests that the DNA-PKcs-mediated YAP1 phosphorylation and the ferroptosis activation could be the promising therapeutic targets for the management of DCM.
Insights
DNA-Dependent Protein Kinase catalytic subunit (DNA-PKcs) activation drives ferroptosis in diabetic cardiomyopathy (DCM). Inhibiting DNA-PKcs or its interaction with YAP1 improves heart function and reduces damage.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Cellular Stress Response
Background:
- Diabetic cardiomyopathy (DCM) involves complex cellular damage pathways.
- The DNA damage response (DDR) is crucial for cellular integrity.
- Hyperglycemia is a known risk factor for cardiovascular complications.
Purpose of the Study:
- To investigate the role of DNA-Dependent Protein Kinase catalytic subunit (DNA-PKcs) in hyperglycemia-induced ferroptosis in DCM.
- To elucidate the molecular mechanisms linking DNA-PKcs, YAP1, and ferroptosis in DCM.
Main Methods:
- Streptozotocin-induced DCM mouse model.
- Genetic deletion of DNA-PKcs in cardiomyocytes.
- Co-immunoprecipitation and Mass Spectrometry (Co-IP/MS) for protein interaction analysis.
- YAP1 phosphorylation site mutant (T226A) knockin mice.
Main Results:
- Significant activation of DNA-PKcs-dependent DDR in DCM.
- DNA-PKcs deletion ameliorated cardiac dysfunction, DNA damage, and inflammation.
- DNA-PKcs directly phosphorylates YAP1 at Thr226, promoting its nuclear retention and ferroptosis gene transcription.
- YAP1 T226A mutant mice showed reduced ferroptosis, fibrosis, and improved cardiac function.
Conclusions:
- DDR acts as a sensor for hyperglycemic stress, activating ferroptosis via the DNA-PKcs-YAP1 axis.
- Targeting DNA-PKcs-mediated YAP1 phosphorylation offers a potential therapeutic strategy for DCM.
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