Necroptosis: (Last) Message in a Bubble

Vandenabeele, Peter; Riquet, Franck B.; Cappe, Benjamin

doi:10.1016/j.immuni.2017.07.002

Cited by 15 publications

(11 citation statements)

References 9 publications

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“…Both studies, however, found that ESCRT can promote cell survival and therefore allow cells to produce more cytokines and chemokines that may contribute to cellular communication. 4,35,36 They also found a physical association of MLKL and the ESCRT complex, using mass spectroscopy as well as western blot, further strengthening the molecular link between necroptosis and membrane remodeling. 35 Although we found no direct binding between MLKL and CHMP4B ( Fig.…”

Section: Discussionmentioning

confidence: 84%

Biological events and molecular signaling following MLKL activation during necroptosis

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 84%

Biological events and molecular signaling following MLKL activation during necroptosis

et al. 2017

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“…Likewise, we found slightly but statistically significantly higher LDH levels due to C2-CER treatment albeit only after 48 h, a result which points at a necrotic form of cell death. Typical morphological signs of necro(pto)sis, including ballooning and cell burst, were evident in the C2-CER treated groups 54 .…”

Section: Discussionmentioning

confidence: 92%

Necroptosis in primate luteolysis: a role for ceramide

Bagnjuk¹,

Stöckl²,

Fröhlich³

et al. 2019

Cell Death Discovery

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The corpus luteum (CL) is a transient endocrine organ, yet molecular mechanisms resulting in its demise are not well known. The presence of phosphorylated mixed lineage kinase domain-like pseudokinase pMLKL(T357/S358) in human and nonhuman primate CL samples (Macaca mulatta and Callithrix jacchus) implied that necroptosis of luteal cells may be involved. In M. mulatta CL, pMLKL positive staining became detectable only from the mid-late luteal phase onwards, pointing to necroptosis during regression of the CL. Cell death, including necroptosis, was previously observed in cultures of human luteal granulosa cells (GCs), an apt model for the study of the human CL. To explore mechanisms of necroptotic cell death in GCs during culture, we performed a proteomic analysis. The levels of 50 proteins were significantly altered after 5 days of culture. Interconnectivity analysis and immunocytochemistry implicated specifically the ceramide salvage pathway to be enhanced. M. mulatta CL transcriptome analysis indicated in vivo relevance. Perturbing endogenous ceramide generation by fumonisin B1 (FB1) and addition of soluble ceramide (C2-CER) yielded opposite actions on viability of GCs and therefore supported the significance of the ceramide pathway. Morphological changes indicated necrotic cell death in the C2-CER treated group. Studies with the pan caspase blocker zVAD-fmk or the necroptosis blocker necrosulfonamid (NSA) further supported that C2-CER induced necroptosis. Our data pinpoint necroptosis in a physiological process, namely CL regression. This raises the possibility that the primate CL could be rescued by pharmacological inhibition of necroptosis or by interaction with ceramide metabolism.

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“…Some models favor direct pore formation 23 , 24 and others mention the requirement for the recruitment of ion channels 25 . Recently, the ESCRT III mechanism has been implicated in the regulation of the formation of MLKL-containing exosomes 50 – 52 . Prophylactic immunization of mice with cancer cells that are dying by necroptosis induced by conditional activation of a RIPK3 transgene construct can induce antitumor immunity 17 , 18 .…”

Section: Discussionmentioning

confidence: 99%

Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes

et al. 2018

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Cancer immunotherapy can induce durable antitumor responses. However, many patients poorly respond to such therapies. Here we describe a generic antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein. This intervention stalls primary tumor growth and protects against distal and disseminated tumor formation in syngeneic mouse melanoma and colon carcinoma models. Moreover, MLKL-mRNA treatment combined with immune checkpoint blockade further improves the antitumor activity. MLKL-mRNA treatment rapidly induces T cell responses directed against tumor neo-antigens and requires CD4+ and CD8+ T cells to prevent tumor growth. Type I interferon signaling and Batf3-dependent dendritic cells are essential for this mRNA treatment to elicit tumor antigen-specific T cell responses. Moreover, MLKL-mRNA treatment blunts the growth of human lymphoma in mice with a reconstituted human adaptive immune system. MLKL-based treatment can thus be exploited as an effective antitumor immunotherapy.

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Necroptosis: (Last) Message in a Bubble

Cited by 15 publications

References 9 publications

Biological events and molecular signaling following MLKL activation during necroptosis

Biological events and molecular signaling following MLKL activation during necroptosis

Necroptosis in primate luteolysis: a role for ceramide

Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes

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