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The Pro-apoptotic STK38 Kinase Is a New Beclin1 Partner Positively Regulating Autophagy
Carine Joffre1, Nicolas Dupont2, Lily Hoa3
1INSERM U830, Institut Curie, Paris 75248, France; Cancer Research Center of Toulouse, UMR1037, Toulouse 31037, France.
Abstract:
Autophagy plays key roles in development, oncogenesis, cardiovascular, metabolic, and neurodegenerative diseases. Hence, understanding how autophagy is regulated can reveal opportunities to modify autophagy in a disease-relevant manner. Ideally, one would want to functionally define autophagy regulators whose enzymatic activity can potentially be modulated. Here, we describe the STK38 protein kinase (also termed NDR1) as a conserved regulator of autophagy. Using STK38 as bait in yeast-two-hybrid screens, we discovered STK38 as a novel binding partner of Beclin1, a key regulator of autophagy. By combining molecular, cell biological, and genetic approaches, we show that STK38 promotes autophagosome formation in human cells and in Drosophila. Upon autophagy induction, STK38-depleted cells display impaired LC3B-II conversion; reduced ATG14L, ATG12, and WIPI-1 puncta formation; and significantly decreased Vps34 activity, as judged by PI3P formation. Furthermore, we observed that STK38 supports the interaction of the exocyst component Exo84 with Beclin1 and RalB, which is required to initiate autophagosome formation. Upon studying the activation of STK38 during autophagy induction, we found that STK38 is stimulated in a MOB1- and exocyst-dependent manner. In contrast, RalB depletion triggers hyperactivation of STK38, resulting in STK38-dependent apoptosis under prolonged autophagy conditions. Together, our data establish STK38 as a conserved regulator of autophagy in human cells and flies. We also provide evidence demonstrating that STK38 and RalB assist the coordination between autophagic and apoptotic events upon autophagy induction, hence further proposing a role for STK38 in determining cellular fate in response to autophagic conditions.
Insights
The STK38 protein kinase (NDR1) is identified as a conserved autophagy regulator. It promotes autophagosome formation and influences cellular fate by coordinating autophagic and apoptotic events.
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- Autophagy is crucial in various physiological and pathological processes, including development, cancer, and neurodegenerative diseases.
- Identifying and understanding autophagy regulators is key to developing therapeutic strategies for related diseases.
- The STK38 protein kinase (NDR1) is explored for its potential role in autophagy regulation.
Purpose of the Study:
- To identify and characterize novel regulators of autophagy.
- To elucidate the molecular mechanisms by which STK38 influences autophagy.
- To investigate the role of STK38 in coordinating autophagic and apoptotic processes.
Main Methods:
- Yeast-two-hybrid screens to identify STK38 binding partners.
- Molecular, cell biological, and genetic approaches in human cells and Drosophila.
- Analysis of autophagy markers (LC3B-II conversion, ATG proteins, WIPI-1 puncta) and Vps34 activity (PI3P formation).
- Investigation of protein-protein interactions involving STK38, Beclin1, Exo84, and RalB.
- Study of STK38 activation mechanisms (MOB1, exocyst-dependent) and its response to RalB depletion.
Main Results:
- STK38 was identified as a novel binding partner of Beclin1 and a conserved autophagy regulator.
- STK38 promotes autophagosome formation, evidenced by enhanced LC3B-II conversion and puncta formation of autophagy-related proteins.
- STK38 facilitates the interaction of Exo84 with Beclin1 and RalB, essential for autophagosome initiation.
- STK38 activation is dependent on MOB1 and the exocyst complex.
- RalB depletion leads to STK38 hyperactivation and apoptosis under prolonged autophagy.
- STK38 plays a role in coordinating autophagic and apoptotic events.
Conclusions:
- STK38 (NDR1) is a conserved protein kinase that functions as a positive regulator of autophagy in human cells and Drosophila.
- STK38 is essential for autophagosome formation by promoting key protein interactions and Vps34 activity.
- STK38 and RalB collaborate to balance autophagic and apoptotic responses, influencing cellular fate during autophagy induction.
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