MLKL Requires the Inositol Phosphate Code to Execute Necroptosis

Dovey, Cole M.; Diep, Jonathan; Clarke, Bradley P.; Hale, Andrew T.; McNamara, Dan E.; Guo, Hongyan; Brown, Nathaniel W.; Cao, Jennifer Yinuo; Grace, Christy R.; Gough, Peter J.; Bertin, John; Dixon, Scott J.; Fiedler, Dorothea; Mocarski, Edward S.; Kaiser, William J.; Moldoveanu, Tudor; York, John D.; Carette, Jan E.

doi:10.1016/j.molcel.2018.05.010

Cited by 126 publications

(174 citation statements)

References 59 publications

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“…Cells with depletion of IP multikinase (IPMK) and inositol-tetrakisphosphate 1-kinase (ITPK1) which are critical for synthesis of cellular IPs were unable to show MLKL membrane association by necroptosis induction, despite the presence of phosphorylated MLKL. In IPMK and ITPK1 complemented cells, the membrane disruption and subsequent necroptosis were restored [70]. Thus, this indicates that IP kinases regulate necroptosis by influencing the plasma membrane association of phosphorylated MLKL.…”

Section: Mlkl Is the Effector Protein In Necroptosismentioning

confidence: 80%

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Chen

Garssen

et al. 2019

Cells

129

115

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Necroptosis, or regulated necrosis, is an important type of programmed cell death in addition to apoptosis. Necroptosis induction leads to cell membrane disruption, inflammation and vascularization. It plays important roles in various pathological processes, including neurodegeneration, inflammatory diseases, multiple cancers, and kidney injury. The molecular regulation of necroptotic pathway has been intensively studied in recent years. Necroptosis can be triggered by multiple stimuli and this pathway is regulated through activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like (MLKL). A better understanding of the mechanism of regulation of necroptosis will further aid to the development of novel drugs for necroptosis-associated human diseases. In this review, we focus on new insights in the regulatory machinery of necroptosis. We further discuss the role of necroptosis in different pathologies, its potential as a therapeutic target and the current status of clinical development of drugs interfering in the necroptotic pathway.

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Section: Mlkl Is the Effector Protein In Necroptosismentioning

confidence: 80%

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Chen

Garssen

et al. 2019

Cells

129

115

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“…It is well-established that InsPs, such as InsP 3 (17) and InsP 4 (16,(18)(19)(20), act as signaling messengers in the activation of immune cells. However, little is understood about the roles of higher order InsPs in immune responses, although they can act as a structural cofactor or an allosteric regulator that modulates the stability and function of protein complex (21)(22)(23). Recently, it has been reported that a mixture of InsP 6 and Btk in solution might enable transient dimerization and transautophosphorylation of Btk (21).…”

mentioning

confidence: 99%

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Kim

Min

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton’s tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.

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“…To undergo necroptosis, MLKL engagement requires the presence of specific lipids at the plasmatic membrane. Phosphatidyl inositol phosphates including, phosphatidylinositol-5-phosphate and phosphatidylinositol-4,5-bisphosphate have been described to function as lipid receptors of MLKL in the inner leaflet of the plasma membrane 55–57 . These lipids are products of kinases that can phosphorylate the 3-, 4-, and 5-hydroxyl groups of the inositol head group of PI lipids 58 .…”

Section: Discussionmentioning

confidence: 99%

Distinct photooxidation-induced cell death pathways lead to selective killing of human breast cancer cells

Santos

Inague²,

Arini

et al. 2020

Preprint

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Lack of effective treatments for aggressive breast cancer is still a major global health problem. We previously reported that Photodynamic Therapy using Methylene Blue as photosensitizer (MB-PDT) massively kills metastatic human breast cancer, marginally affecting healthy cells. In this study we aimed to unveil the molecular mechanisms behind MB-PDT effectiveness. Through lipidomic and biochemical approaches we demonstrated that MB-PDT efficiency and specificity relies on polyunsaturated fatty acids-enriched membranes and on the better capacity to deal with photooxidative damage displayed by non-tumorigenic cells. We found out that, in tumorigenic cells, lysosome membrane permeabilization is accompanied by ferroptosis and/or necroptosis. Our results broadened the understanding of MB-PDT-induced photooxidation mechanisms and specificity in breast cancer cells. Therefore, we demonstrated that efficient approaches could be designed on the basis of lipid composition and metabolic features for hard-to-treat cancers. The results further reinforce MB-PDT as a therapeutic strategy for highly aggressive human breast cancer cells.

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MLKL Requires the Inositol Phosphate Code to Execute Necroptosis

Cited by 126 publications

References 59 publications

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Distinct photooxidation-induced cell death pathways lead to selective killing of human breast cancer cells

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