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Deficiency of transcriptional regulator p8 induces autophagy and causes impaired cardiac function

Derek K Kong, Serban P Georgescu, John M Kyriakis

    Autophagy
    |February 4, 2017
    PubMed

    Insights

    The transcriptional regulator p8 controls autophagy by inhibiting FoxO3 activity. Loss of p8 enhances autophagy, reduces cell viability, and causes cardiac dysfunction in mice, revealing a new role for p8 in cellular homeostasis and disease.

    Area of Science:

    • Cellular Biology
    • Molecular Biology
    • Physiology

    Background:

    • Autophagy is a cellular process crucial for nutrient recycling and waste removal.
    • Dysregulation of autophagy is linked to diseases like cancer, neurodegeneration, and cardiomyopathies.
    • The transcription factor FoxO3 is a known activator of autophagy.

    Purpose of the Study:

    • To investigate the role of the transcriptional regulator p8 in controlling autophagy.
    • To elucidate the mechanism by which p8 influences the FoxO3-mediated autophagy pathway.
    • To examine the in vivo consequences of p8 deficiency on cardiac function.

    Main Methods:

    • Investigated p8's effect on FoxO3 transcriptional activity and its target gene, Bnip3.
    • Utilized cell culture models with p8 silencing and overexpression.
    • Assessed cellular viability and autophagy levels.
    • Examined cardiac function and autophagy markers in p8 knockout mice.

    Main Results:

    • p8 represses FoxO3 transcriptional activity, thereby inhibiting autophagy.
    • p8 silencing increases basal autophagy, Bnip3 expression, and decreases cellular viability.
    • p8 deficiency in mice leads to increased cardiac autophagy and impaired heart function.
    • Bnip3 knockdown rescues the viability defect in p8-deficient cells.

    Conclusions:

    • p8 acts as a negative regulator of autophagy by antagonizing the FoxO3-Bnip3 axis.
    • p8 plays a critical role in maintaining cellular homeostasis and preventing cardiac pathology.
    • Targeting the p8-FoxO3 pathway may offer therapeutic strategies for autophagy-related diseases.

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