Biological events and molecular signaling following MLKL activation during necroptosis

Abstract

Necroptosis is a form of programmed necrotic cell death mediated by the kinase RIPK3 and its substrate MLKL. MLKL, which displays plasma membrane (PM) pore-forming activity upon phosphorylation, functions as the executioner during necroptosis. Thus, it was previously assumed that MLKL phosphorylation is the endpoint of the necroptotic signaling pathway. Here, we summarize several events that characterize the dying necroptotic cells after MLKL phosphorylation, including Ca influx, phosphatidylserine (PS) externalization, PM repair by ESCRT-III activation, and the final compromise of PM integrity. These processes add several unexpected regulatory events downstream of MLKL signaling. We have also observed that CoCl, which may mimic hypoxia, can induce necroptosis, which suggests that in vivo triggers of necroptosis might include a transient lack of O.

Pannexin-1 Channels govern the Generation of Necroptotic small Extracellular Vesicles

“…1A-D). Supporting an initial observation by Gong et al [17], staining with TO-PRO-3 discriminated a population of "leaky" cells with a dim staining from dead cells with a high incorporation of the dye (Fig. 1C and 1E).…”

“…Moreover, "leakiness" preceded full permeabilization to the dye seen after 24 hours, which likely reflects the loss of PM integrity (Ref. [17], Fig. 1F and 1G).…”

“…These data identify a novel signaling nexus between MLKL, Rab27, and PANX1, and propose ways to interfere with small EV generation.allows the pseudokinase to insert into the PM and compromise cell-membrane integrity leading to the cell's demise [10][11][12][13][14].Shortly before PM collapses, MLKL oligomers trigger the exposure of phosphatidylserine (PS) residues at the cell surface, acting as "eat-me" signals for the surrounding immune cells [15,16]. However, cells with phosphorylated MLKL and flipped PS are not necessarily committed to death and can "resuscitate" provided the stimulus is removed in a timely manner [16,17]. MLKL also governs the dynamic biogenesis and release of small extracellular vesicles (EVs) during the early stages of necroptosis by cells which are otherwise viable [15,18].…”

The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

“…Phosphorylated MLKL oligomerizes and translocates to the plasma membrane, forming pores to directly execute a necrotic form of cell death (Petrie et al, 2019;Sun et al, 2012). The mechanisms by which MLKL triggers necroptosis are still under debate, but possibly depend on the cell type affected (Gong et al, 2017;Petrie et al, 2017;Zhang et al, 2016a). Other studies suggested that MLKL interacts with the cation channel TRPM7, leading to abnormal calcium influx leading to cell swelling and plasma membrane rupture (Cai et al 2014).…”

To the edge of cell death and back

“…However, several recent studies provide convincing evidence that this tenant of cell death may be more capricious than first assumed, as cells can survive/recover after experiencing a transient engagement of the cell death machinery [2][3][4][5]. Since these surviving cells are not eliminated, they may be endowed with new biological features and thus, may play critical roles in various physiological contexts [1,6]. In this review, we discuss the biology of cellular recovery and the underlying mechanisms that may govern it.…”