Journal article
BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux
B Reljic, S Conos, EF Lee, JM Garnier, L Dong, G Lessene, WD Fairlie, DL Vaux, LM Lindqvist
Autophagy | TAYLOR & FRANCIS INC | Published : 2016
Abstract
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..
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Awarded by National Health and Medical Research Council (NHMRC) Program
Awarded by NHMRC Peter Doherty Early Career Fellowship
Awarded by NHMRC Career Development Fellowship
Awarded by NHMRC Senior Principal Research Fellowship
Funding Acknowledgements
Funding for this project was provided by National Health and Medical Research Council (NHMRC) Program Grant 1020136 and Project Grant 1049949. LML holds an NHMRC Peter Doherty Early Career Fellowship (1035502), EFL holds an NHMRC Career Development Fellowship (1024620), and DLV a NHMRC Senior Principal Research Fellowship (1020136). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS and from support from the Australian Cancer Research Fund.