ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.

中文翻译：

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ATG4B的MST4磷酸化可调节胶质母细胞瘤的自噬活性，致瘤性和抗辐射性。

ATG4B通过可逆修饰ATG8促进自噬体形成，从而刺激自噬。我们确定ATG4B为哺乳动物不育20样激酶（STK）26 / MST4的底物。MST4使丝氨酸残基383处的ATG4B磷酸化，从而刺激ATG4B活性并增加自噬通量。使用遗传方法或ATG4B抑制剂抑制MST4或ATG4B活性可抑制自噬和胶质母细胞瘤（GBM）细胞的致瘤性。此外，辐射诱导MST4表达，ATG4B磷酸化和自噬。与颅内GBM异种移植一起治疗小鼠时，抑制ATG4B联合放疗可显着减慢肿瘤生长，并提供显着的生存益处。我们的工作描述了影响GBM自噬和恶性肿瘤的MST4-ATG4B信号传导轴，