The pro-apoptotic STK38 kinase is a new Beclin1 Partner positively regulating autophagy

Carine Joffre, Nicolas Dupont, Lily Hoa, Valenti Gomez, Raul Pardo, Catarina Gonçalves-Pimentel, Pauline Achard, Audrey Bettoun, Brigitte Meunier, Chantal Bauvy, Ilaria Cascone, Patrice Codogno*, Manolis Fanto, Alexander Hergovich, Jacques Camonis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)
228 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2479-2492
Number of pages14
JournalCurrent Biology
Volume25
Issue number19
Early online date17 Sept 2015
DOIs
Publication statusPublished - 5 Oct 2015

Fingerprint

Dive into the research topics of 'The pro-apoptotic STK38 kinase is a new Beclin1 Partner positively regulating autophagy'. Together they form a unique fingerprint.

Cite this