Abstract
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.
- Received May 28, 2018.
- Accepted January 25, 2019.
- © 2019. Published by The Company of Biologists Ltd
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