Activated MLKL attenuates autophagy following its translocation to intracellular membranes
- J Cell Sci. 2019 Feb 28;132(5):jcs220996. doi: 10.1242/jcs.220996.
- 1. Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia.
- 2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050, Australia.
- 3. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050, Australia [email protected] [email protected].
- 4. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia.
- 5. Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia [email protected] [email protected].
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 (also known as MAP1LC3B), 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 autophagosome and/or autolysosome function, and required the association of activated MLKL with intracellular membranes. Collectively, our findings uncover an additional role for the MLKL pseudokinase, namely to inhibit Autophagy during Necroptosis.