title: LAMTOR1 depletion induces p53-dependent apoptosis via aberrant lysosomal activation.
abstract: Lysosomal regulation is a poorly understood mechanism that is central to degradation and recycling processes. Here we report that LAMTOR1 (late endosomal/lysosomal adaptor, MAPK and mTOR activator 1) downregulation affects lysosomal activation, through mechanisms that are not solely due to mTORC1 inhibition. LAMTOR1 depletion strongly increases lysosomal structures that display a scattered intracellular positioning. Despite their altered positioning, those dispersed structures remain overall functional: (i) the trafficking and maturation of the lysosomal enzyme cathepsin B is not altered; (ii) the autophagic flux, ending up in the degradation of autophagic substrate inside lysosomes, is stimulated. Consequently, LAMTOR1-depleted cells face an aberrant lysosomal catabolism that produces excessive reactive oxygen species (ROS). ROS accumulation in turn triggers p53-dependent cell cycle arrest and apoptosis. Both mTORC1 activity and the stimulated autophagy are not necessary to this lysosomal cell death pathway. Thus, LAMTOR1 expression affects the tuning of lysosomal activation that can lead to p53-dependent apoptosis through excessive catabolism.
authors.affiliation: Université de Lyon, Lyon F-69000, France.
authors.forename: M
authors.initials: M
authors.lastname: Malek
authors.forename: P
authors.initials: P
authors.lastname: Guillaumot
authors.forename: A-L
authors.initials: AL
authors.lastname: Huber
authors.forename: J
authors.initials: J
authors.lastname: Lebeau
authors.forename: V
authors.initials: V
authors.lastname: Pétrilli
authors.forename: A
authors.initials: A
authors.lastname: Kfoury
authors.forename: I
authors.initials: I
authors.lastname: Mikaelian
authors.forename: T
authors.initials: T
authors.lastname: Renno
authors.forename: S N
authors.initials: SN
authors.lastname: Manié
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C544374:LAMTOR1 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002401:Cathepsin B