title: BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux.
abstract: Inhibition of prosurvival BCL2 family members can induce autophagy, but the mechanism is controversial. We have provided genetic evidence that BCL2 family members block autophagy by inhibiting BAX and BAK1, but others have proposed they instead inhibit BECN1. Here we confirm that small molecule BH3 mimetics can induce BAX- and BAK1-independent MAP1LC3B/LC3B lipidation, but this only occurred at concentrations far greater than required to induce apoptosis and dissociate canonical BH3 domain-containing proteins that bind more tightly than BECN1. Because high concentrations of a less-active enantiomer of ABT-263 also induced BAX- and BAK1-independent LC3B lipidation, induction of this marker of autophagy appears to be an off-target effect. Indeed, robust autophagic flux was not induced by BH3 mimetic compounds in the absence of BAX and BAK1. Therefore at concentrations that are on target and achievable in vivo, BH3 mimetics only induce autophagy in a BAX- and BAK1-dependent manner.
authors.affiliation: a Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria, Australia.|b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Reljic
authors.affiliation: a Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria, Australia.|b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Conos
authors.affiliation: b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.|c Structural Biology Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria , Australia.|d Olivia Newton-John Cancer Research Institute , Heidelberg , Victoria , Australia.|e School of Cancer Medicine, La Trobe University , Melbourne , Victoria , Australia.|f Department of Chemistry and Physics , La Trobe Institute for Molecular Science , Melbourne , Victoria , Australia.
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.affiliation: b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.|g Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria , Australia.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Garnier
authors.affiliation: a Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria, Australia.|b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.
authors.forename: Li
authors.initials: L
authors.lastname: Dong
authors.affiliation: b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.|g Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria , Australia.|h Department of Pharmacology and Therapeutics , University of Melbourne , Parkville , Victoria , Australia.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.affiliation: b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.|c Structural Biology Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria , Australia.|d Olivia Newton-John Cancer Research Institute , Heidelberg , Victoria , Australia.|e School of Cancer Medicine, La Trobe University , Melbourne , Victoria , Australia.|f Department of Chemistry and Physics , La Trobe Institute for Molecular Science , Melbourne , Victoria , Australia.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Fairlie
authors.affiliation: a Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria, Australia.|b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: a Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research , Melbourne , Victoria, Australia.|b Department of Medical Biology , University of Melbourne , Parkville , Victoria , Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Lindqvist
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C579720:venetoclax; C528561:navitoclax
keywords: ABT-199; ABT-263; ABT-737; BCL2; BECN1; autophagy