A Receptor-interacting Protein 1 (Rip1) Independent Necrotic Death Under The Control Of Protein Phosphatase Pp2a That Involves The Reorganization Of Actin Cytoskeleton And The Action Of Cofilin-1 [Cell Biology]

August 5th, 2014 by Tomasella, A., Blangy, A., Brancolini, C.

Cell death by necrosis is emerging not merely as a passive phenomenon but as a cell-regulated process. Here, by using different necrotic triggers we prove the existence of two distinct necrotic pathways. The mitochondrial ROS generator DMNQ elicits classical necroptosis with the involvement of RIP1 and Drp1. On the opposite G5, a non-selective isopeptidase inhibitor triggers a distinct necrotic pathway that depends on the protein phosphatase PP2A and the actin cytoskeleton. PP2A catalytic subunit is stabilized by G5 treatment and its activity is increased. Furthermore PP2Ac accumulates into the cytoplasm during necrosis similarly to HMGB1. We have also defined in the actin binding protein cofilin-1 a link between PP2A, actin cytoskeleton and necrotic death. Cofilin-1 severing/depolymerization activity is negatively regulated by phosphorylation of serine 3. PP2A contributes to the dephosphorylation of serine 3 elicited by G5. Finally, a cofilin mutant that mimics phosphorylated Ser 3 can partially rescue necrosis in response to G5.
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