title: The Pro-apoptotic STK38 Kinase Is a New Beclin1 Partner Positively Regulating Autophagy.
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.
authors.affiliation: INSERM U830, Institut Curie, Paris 75248, France; Cancer Research Center of Toulouse, UMR1037, Toulouse 31037, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Joffre
authors.affiliation: INSERM U1151-CNRS UMR 8253, Institut Necker Enfants-Malades, Paris 75993, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupont
authors.affiliation: University College London, Cancer Institute, London WC1E 6BT, UK.
authors.forename: Lily
authors.initials: L
authors.lastname: Hoa
authors.affiliation: University College London, Cancer Institute, London WC1E 6BT, UK.
authors.forename: Valenti
authors.initials: V
authors.lastname: Gomez
authors.affiliation: Department of Basic and Clinical Neuroscience, Kings College London, London SE5 9NU, UK.
authors.forename: Raul
authors.initials: R
authors.lastname: Pardo
authors.affiliation: Department of Basic and Clinical Neuroscience, Kings College London, London SE5 9NU, UK.
authors.forename: Catarina
authors.initials: C
authors.lastname: Gonçalves-Pimentel
authors.affiliation: Cancer Research Center of Toulouse, UMR1037, Toulouse 31037, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Achard
authors.affiliation: INSERM U830, Institut Curie, Paris 75248, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bettoun
authors.affiliation: INSERM U830, Institut Curie, Paris 75248, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
authors.affiliation: INSERM U1151-CNRS UMR 8253, Institut Necker Enfants-Malades, Paris 75993, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Bauvy
authors.affiliation: INSERM U830, Institut Curie, Paris 75248, France.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cascone
authors.affiliation: INSERM U1151-CNRS UMR 8253, Institut Necker Enfants-Malades, Paris 75993, France. Electronic address: patrice.codogno@inserm.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.affiliation: Department of Basic and Clinical Neuroscience, Kings College London, London SE5 9NU, UK. Electronic address: manolis.fanto@kcl.ac.uk.
authors.forename: Manolis
authors.initials: M
authors.lastname: Fanto
authors.affiliation: University College London, Cancer Institute, London WC1E 6BT, UK. Electronic address: a.hergovich@ucl.ac.uk.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
authors.affiliation: INSERM U830, Institut Curie, Paris 75248, France. Electronic address: jacquescamonis@gmail.com.
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004330:Drosophila; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human