title: Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation.
abstract: The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting lysosome function, while others were developed to activate the pathway. Here, we report the surprising finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes. Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together, our data raise important issues regarding the interpretation of LC3 lipidation data and the use of autophagy modulators, and highlight the need for a greater understanding of the functional consequences of noncanonical autophagy.
authors.affiliation: a Signalling Programme , The Babraham Institute , Babraham , UK.
authors.forename: Elise
authors.initials: E
authors.lastname: Jacquin
authors.affiliation: b Department of Pathology , Necker-Enfants Malades Hospital , MAGEC-Necker Team , Paris , France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Leclerc-Mercier
authors.affiliation: c Université de Franche-Comté , Besancon , France.
authors.forename: Celine
authors.initials: C
authors.lastname: Judon
authors.affiliation: d Centre Hospitalier Régional Universitaire , University François-Rabelais, Faculty of Medicine , Tours , France.|e INSERM , U966 , Tours , France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Blanchard
authors.affiliation: b Department of Pathology , Necker-Enfants Malades Hospital , MAGEC-Necker Team , Paris , France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fraitag
authors.affiliation: a Signalling Programme , The Babraham Institute , Babraham , UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Florey
mesh_terms: D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids; D008247:Lysosomes / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*
chemical_list: D008055:Lipids; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins
keywords: LAP; autophagy; lipidation; lysosome; lysosomotropic; noncanonical