Abstract

Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5′ AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak-triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak-mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-β (IFN-β) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis.

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Acknowledgements

We thank J. Bernadini, S. Iyer, I. Tan, and G. Dewson (WEHI) for helpful discussions and technical assistance. S63845 was a kind gift from C. Burns (WEHI). Funding for this project was provided by NHMRC Program Grants 461221 (D.L.V.) and 1016647 (B.T.K.) and Project Grant 1106471 (M.L.). L.M.L. was supported by an NHMRC Peter Doherty Early Career Fellowship 1035502, and D.L.V. and B.T.K. held NHMRC Fellowships (1020136 and 1063008, respectively). J.S.O. (130100988) and M.L. (1601100063) are ARC Future Fellows and K.M. is supported by an Australian Federal Government Postgraduate Award. This work was made possible through Independent Research Institutes Infrastructure Support Scheme Grant (361646) from the Australian National Health and Medical Research Council and a Victorian State Government Operational Infrastructure Support Grant.

Author contributions

L.M.L., D.F., K.M. and T.A.D. performed the experiments; L.M.L., D.F., K.M., J.S.O. and B.T.K. designed the experiments; and L.M.L., K.M., M.L. and B.T.K. analysed the data. L.M.L., B.T.K. and D.L.V. wrote the manuscript.

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  1. Edited by S. Kumar

Affiliations

  1. Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC, 3052, Australia

    • Lisa M. Lindqvist
    • , Daniel Frank
    •  & David L. Vaux
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3050, Australia

    • Lisa M. Lindqvist
    • , Daniel Frank
    • , Kate McArthur
    • , Benjamin T. Kile
    •  & David L. Vaux
  3. Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC, 3052, Australia

    • Kate McArthur
    •  & Benjamin T. Kile
  4. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    • Kate McArthur
    •  & Benjamin T. Kile
  5. Department of Medicine, Metabolic Signalling Laboratory, St Vincent’s Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia

    • Toby A. Dite
    •  & Jonathan S. Oakhill
  6. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia

    • Michael Lazarou

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Conflict of interest

D.L.V. used to be on the scientific advisory board for TetraLogic Pharmaceuticals.

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Correspondence to Lisa M. Lindqvist.

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https://doi.org/10.1038/s41418-017-0017-z