Necroptotic MLKL attenuates autophagy following its translocation to intracellular membranes
Publication Year 2019-02-11, Volume 132, Issue #5, Page pii: jcs220996
- Journal Title
- Journal of Cell Science
- Publication Type
- Journal Article
- Necroptosis is an inflammatory form of programmed cell death mediated by the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Upon phosphorylation by receptor-interacting protein kinase-3 (RIPK3), MLKL oligomerizes, and translocates to and disrupts the plasma membrane, thereby causing necroptotic cell lysis. Herein, we show that activation of necroptosis in mouse dermal fibroblasts (MDFs) and HT-29 human colorectal cancer cells results in accumulation of the autophagic marker, lipidated LC3B, in an MLKL-dependent manner. Unexpectedly, the necroptosis-induced increase in lipidated LC3B was due to inhibition of autophagic flux, not the activation of autophagy. Inhibition of autophagy by MLKL correlated with a decrease in auto/lysosomal function, and required the association of activated MLKL with intracellular membranes. Collectively, our findings uncover an additional role of the MLKL pseudokinase, namely to inhibit autophagy during necroptosis.
- WEHI Research Division(s)
- Inflammation; Blood Cells And Blood Cancer
- PubMed ID
- Publisher's Version
- NHMRC Grants
- NHMRC/461221, NHMRC/1101405, NHMRC/1145788, NHMRC/1105754, NHMRC/1141466, NHMRC/1020136,
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-03-13 08:04:16Last Modified: 2019-03-13 08:54:38