Review
Medicine, Research & Experimental
Ming Yang, Wei Chen, Liyu He, Di Liu, Li Zhao, Xi Wang
Summary: This study reviews the molecular mechanism of necroptosis and discusses its role in the pathogenesis of various diseases. Additionally, it summarizes several inhibitors of necroptosis and discusses the potential of targeting necroptosis as a therapeutic strategy for various diseases.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Multidisciplinary Sciences
Sarah E. Garnish, Yanxiang Meng, Akiko Koide, Jarrod J. Sandow, Eric Denbaum, Annette V. Jacobsen, Wayland Yeung, Andre L. Samson, Christopher R. Horne, Cheree Fitzgibbon, Samuel N. Young, Phoebe P. C. Smith, Andrew I. Webb, Emma J. Petrie, Joanne M. Hildebrand, Natarajan Kannan, Peter E. Czabotar, Shohei Koide, James M. Murphy
Summary: Phosphorylation of MLKL by RIPK3 kinase leads to MLKL oligomerization, translocation, and membrane permeabilization to induce cell death. Monobodies can bind to the MLKL pseudokinase domain, revealing distinct conformations during activation and disengagement from RIPK3, a key regulatory step in necroptosis. These structural and functional studies shed light on the mechanism of MLKL activation and regulation in necroptosis.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Rebekka Karlowitz, Sjoerd J. L. van Wijk
Summary: Lytic forms of programmed cell death, such as necroptosis, involve cell rupture, release of cellular contents, and triggering of inflammatory responses. Necroptosis has been found to play important roles in human diseases like cancer, infections, and ischaemia/reperfusion injury. Interactions between RIPK1, RIPK3, and MLKL lead to the formation of a death complex called the necrosome, which triggers MLKL-mediated membrane rupture and necroptotic cell death. Post-translational modifications, especially phosphorylation, tightly control necroptotic cell death.
Review
Pharmacology & Pharmacy
Imran Khan, Abdelrahman Yousif, Mikhail Chesnokov, Linda Hong, IIana Chefetz
Summary: Programmed cell death (PCD) has been a major research interest in the past three decades. Initially, apoptosis was considered the only mechanistic pathway for PCD, but now other important pathways such as necroptosis have been discovered, which are crucial for understanding the cellular processes behind different pathological conditions. Additionally, research on triggering necroptosis in cancer cells to induce cell death and overcome chemoresistance is being discussed.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Cell Biology
Wulf Tonnus, Sophie Locke, Claudia Meyer, Francesca Maremonti, Lena Eggert, Anne von Massenhausen, Stefan R. Bornstein, Douglas R. Green, Andreas Linkermann
Summary: RUBCN-deficient mice are hypersensitive to kidney injury, particularly in ischemia-reperfusion injury and cisplatin-induced acute kidney injury models. Combined deficiency of RUBCN and MLKL partially reverses the sensitivity in the ischemia-reperfusion injury model. However, there was no significant difference in overall survival following TNF-alpha injection in RUBCN-deficient mice. Additionally, the absence of GSDMD in RUBCN-deficient mice did not reverse the AKI phenotype.
CELL DEATH & DISEASE
(2022)
Review
Cell Biology
Qi Zhang, Xin-xing Wan, Xi-min Hu, Wen-juan Zhao, Xiao-xia Ban, Yan-xia Huang, Wei-tao Yan, Kun Xiong
Summary: Stem cell therapies show promising effects in restoring damaged tissue, but multiple types of programmed cell death post-transplantation can compromise their efficiency. Understanding and targeting cell death signaling pathways are crucial for successful stem cell therapies in treating diabetes and related diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Wulf Tonnus, Claudia Meyer, Christian Steinebach, Alexia Belavgeni, Anne von Maessenhausen, Nadia Zamora Gonzalez, Francesca Maremonti, Florian Gembardt, Nina Himmerkus, Markus Latk, Sophie Locke, Julian Marschner, Wenjun Li, Spencer Short, Sebastian Doll, Irina Ingold, Bettina Proneth, Christoph Daniel, Nazanin Kabgani, Rafael Kramann, Stephen Motika, Paul J. Hergenrother, Stefan R. Bornstein, Christian Hugo, Jan Ulrich Becker, Kerstin Amann, Hans-Joachim Anders, Daniel Kreisel, Derek Pratt, Michael Guetschow, Marcus Conrad, Andreas Linkermann
Summary: This study demonstrates the role of ferroptosis in acute kidney injury and how dysfunction of Gpx4 can hypersensitize mice to tubular damage. The researchers developed a dual inhibitor targeting RIPK1 and ferroptosis, which improved survival rates in mouse models of acute kidney injury.
NATURE COMMUNICATIONS
(2021)
Review
Immunology
Jianan Zhao, Kai Wei, Ping Jiang, Cen Chang, Lingxia Xu, Linshuai Xu, Yiming Shi, Shicheng Guo, Yu Xue, Dongyi He
Summary: Gout is a chronic inflammatory arthritis disease characterized by hyperuricemia and triggered by interactions among various factors. Recent studies have shown that multiple programmed cell death pathways are involved in the inflammatory response, contributing to the initiation of inflammation.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Veronica Martinez-Osorio, Yasmin Abdelwahab, Uris Ros
Summary: Necroptosis is a regulated cell death pathway characterized by disruption of plasma membrane integrity and release of intracellular content. The protein MLKL plays a crucial role in mediating the final step of plasma membrane permeabilization in this pathway. Despite progress in understanding necroptosis and MLKL biology, the precise mechanism of MLKL function is still unclear. This review discusses key steps in MLKL activation, potential models for its role as a "death executor" in necroptosis, and its emerging alternative functions. It also summarizes the current understanding of MLKL in human disease and provides an overview of strategies targeting MLKL for intervention in necroptosis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Carly DeAntoneo, Pranav Danthi, Siddharth Balachandran
Summary: Mammalian orthoreoviruses (ReoV) are non-pathogenic viruses, but can cause mild gastroenteritis and inflammatory conditions in young children. The ReoV strain Type 3 Dearing (T3D) is being tested as an oncolytic agent, as it can infect tumor cells and activate different cell death pathways, including apoptosis, autophagy, pyroptosis, and necroptosis. ReoV-induced necroptosis, a highly inflammatory form of cell death, may contribute to oncolysis by promoting necrotic lysis of infected cells and provoking beneficial anti-tumor immune responses in the tumor microenvironment.
Article
Pharmacology & Pharmacy
Qi Zhao, Yanbo Zheng, Xing Lv, Jianhua Gong, Lijun Yang
Summary: IMB5036, a novel pyridazinone compound, exhibits potent cytotoxicity against pancreatic cancer cells by inducing necroptosis, leading to inhibiting tumor growth.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2022)
Review
Multidisciplinary Sciences
Kim Newton, Vishva M. Dixit, Nobuhiko Kayagaki
Summary: Inflammatory processes are crucial for tissue repair and pathogen elimination, but excessive or chronic inflammation can lead to diseases such as arthritis and COVID-19. Different cell death mechanisms like apoptosis, necroptosis, and pyroptosis may contribute to inflammatory diseases. Inhibiting cell death and targeting specific mediators of lytic cell death could be potential therapeutic strategies.
Review
Cell Biology
Chang Liu, Zecheng Jiang, Zhongjie Pan, Liang Yang
Summary: Atherosclerosis is a chronic inflammatory vascular disease, and macrophages play a significant role in its progression. Recent studies have highlighted the critical role of programmed cell death in macrophages in the development of vulnerable plaques in atherosclerosis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Immunology
Jianan Zhao, Ping Jiang, Shicheng Guo, Steven J. Schrodi, Dongyi He
Summary: Rheumatoid arthritis is a chronic inflammatory joint disease characterized by chronic synovial inflammation and degeneration of bones and joints. Despite the variety of treatment options available, some patients still have a poor prognosis due to the complex mechanism of the disease. Programmed cell death has been identified as one of the essential pathological mechanisms of RA, contributing to its development through dysregulation in various cell types.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Jie Zhang, Luxia Song, Jundi Jia, Wende Tian, Runmin Lai, Zihao Zhang, Jingen Li, Jianqing Ju, Hao Xu
Summary: From 2012 to 2021, a total of 3,111 research articles on necroptosis were published in 786 academic journals by 19,687 authors in 885 institutions from 82 countries/regions. The majority of publications were from China and the United States, with the United States maintaining the dominant position in necroptosis research. Current necroptosis studies focus on its cross-talk with other types of cell death, potential applications in disease treatment, and further mechanisms. The trending research areas include the synergy with ferroptosis, further RIPK1/RIPK3/MLKL studies, and its association with inflammation and oxidative stress for translational applications in treating cancer and neurodegenerative diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Andre L. Samson, Cheree Fitzgibbon, Komal M. Patel, Joanne M. Hildebrand, Lachlan W. Whitehead, Joel S. Rimes, Annette V. Jacobsen, Christopher R. Horne, Xavier J. Gavin, Samuel N. Young, Kelly L. Rogers, Edwin D. Hawkins, James M. Murphy
Summary: This study presents a toolbox of antibodies for immunofluorescent detection of core necroptosis effectors RIPK1, RIPK3, and MLKL in human and mouse cells. The researchers found that not all commonly used antibodies are suitable for monitoring necroptosis through immunofluorescence microscopy, and methanol fixation is preferred for robust detection of specific RIPK1, RIPK3, and MLKL signals.
CELL DEATH AND DIFFERENTIATION
(2021)
Review
Immunology
Ashley Weir, Sebastian Hughes, Maryam Rashidi, Joanne M. Hildebrand, James E. Vince
Summary: The necroptotic cell death pathway and the role of MLKL in triggering inflammatory responses have been studied extensively. MLKL has diverse functions contributing to the inflammatory nature of necroptosis. MLKL-driven responses activate inflammasome complexes and innate lymphoid cells, leading to disease progression.
CURRENT OPINION IN IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Andre L. Samson, Sarah E. Garnish, Joanne M. Hildebrand, James M. Murphy
Summary: Necroptosis is a lytic, proinflammatory cell death pathway that plays a role in host defense, but can contribute to the pathology of various diseases when dysregulated. The signaling chronology along the RIPK1-RIPK3-MLKL axis and the subcellular compartmentalization of signaling events are crucial for the initiation and execution of necroptosis. A network of modulators surrounding the necroptotic signaling core tunes necroptosis in a context-, cell type-, and species-dependent manner, making it a robust and emergency form of cell death.
Article
Cell Biology
Joanne M. Hildebrand, Bernice Lo, Sara Tomei, Valentina Mattei, Samuel N. Young, Cheree Fitzgibbon, James M. Murphy, Abeer Fadda
Summary: The study identified a very rare heterozygous damaging mutation in MLKL, a gene associated with necroptosis, exclusively in diabetic family members, suggesting a potential role of impaired necroptosis in diabetes. On the other hand, a previously reported damaging mutation in PDX1 was found in a healthy sibling in the same family. These findings highlight the importance of family studies in understanding MODY's incomplete penetrance and support the involvement of dysregulated necroptosis in human disease.
CELL DEATH & DISEASE
(2021)
Article
Multidisciplinary Sciences
Sarah E. Garnish, Yanxiang Meng, Akiko Koide, Jarrod J. Sandow, Eric Denbaum, Annette V. Jacobsen, Wayland Yeung, Andre L. Samson, Christopher R. Horne, Cheree Fitzgibbon, Samuel N. Young, Phoebe P. C. Smith, Andrew I. Webb, Emma J. Petrie, Joanne M. Hildebrand, Natarajan Kannan, Peter E. Czabotar, Shohei Koide, James M. Murphy
Summary: Phosphorylation of MLKL by RIPK3 kinase leads to MLKL oligomerization, translocation, and membrane permeabilization to induce cell death. Monobodies can bind to the MLKL pseudokinase domain, revealing distinct conformations during activation and disengagement from RIPK3, a key regulatory step in necroptosis. These structural and functional studies shed light on the mechanism of MLKL activation and regulation in necroptosis.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Sarah E. Garnish, Joanne M. Hildebrand
Summary: This article reviews the human gene variants associated with the core necroptotic machinery, with a focus on genes encoding MLKL. These natural experiments not only enrich our understanding of the basic biology of necroptosis, but also offer important population-level insights into which clinical indications are most likely to benefit from necroptosis-targeted drugs.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Article
Biochemistry & Molecular Biology
Ashish Sethi, Christopher R. Horne, Cheree Fitzgibbon, Karyn Wilde, Katherine A. Davies, Sarah E. Garnish, Annette Jacobsen, Andre L. Samson, Joanne M. Hildebrand, Ahmad Wardak, Peter E. Czabotar, Emma J. Petrie, Paul R. Gooley, James M. Murphy
Summary: Necroptosis is a programmed cell death pathway that is often deregulated in inflammatory diseases. This study identifies the membrane binding epitope of mouse MLKL and reveals differences in structure and epitope between mouse and human MLKL. These findings highlight the versatility of the 4HB domain.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Multidisciplinary Sciences
Daniel Frank, Sarah E. Garnish, Jarrod J. Sandow, Ashley Weir, Lin Liu, Elise Clayer, Lizeth Meza, Maryam Rashidi, Simon A. Cobbold, Simon R. Scutts, Marcel Doerflinger, Holly Anderton, Kate E. Lawlor, Najoua Lalaoui, Andrew J. Kueh, Vik Ven Eng, Rebecca L. Ambrose, Marco J. Herold, Andre L. Samson, Rebecca Feltham, James M. Murphy, Gregor Ebert, Jaclyn S. Pearson, James E. Vince
Summary: This study reveals that RIPK3 is ubiquitylated on K469, which can limit RIPK3-mediated apoptosis and necroptosis. Mutations in other ubiquitylated residues of RIPK3 increase RIPK3 hyper-ubiquitylation and cell death.
Article
Biochemistry & Molecular Biology
Catia L. Pierotti, Annette V. Jacobsen, Christoph Grohmann, Ruby K. Dempsey, Nima Etemadi, Joanne M. Hildebrand, Cheree Fitzgibbon, Samuel N. Young, Katherine A. Davies, Wilhelmus J. A. Kersten, John Silke, Kym N. Lowes, David C. S. Huang, Mark F. van Delft, James M. Murphy, Guillaume Lessene
Summary: Necroptosis is a form of programmed cell death executed by MLKL pseudokinase. A study found that ABT-869, a tyrosine kinase inhibitor of VEGFR and PDGFR, is able to inhibit necroptosis. Further investigation revealed that ABT-869 targets RIPK1 kinase.
BIOCHEMICAL JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Emma C. Tovey C. Crutchfield, Sarah E. Garnish, Jessica Day, Holly Anderton, Shene Chiou, Anne Hempel, Cathrine Hall, Komal M. Patel, Pradnya Gangatirkar, Katherine R. Martin, Connie S. N. Li Wai Suen, Alexandra L. Garnham, Andrew J. Kueh, Ian P. Wicks, John Silke, Ueli Nachbur, Andre L. Samson, James M. Murphy, Joanne M. Hildebrand
Summary: MLKL and RIPK3 are core signaling proteins of the necroptosis pathway, which is involved in human disease. Necroptosis has been implicated in disease progression in multiple physiological systems and recent studies suggest its role in aging. In this study, we analyzed age-related histopathological and immunological phenotypes in Mlkl(-/-) and Ripk3(-/-) mice. We found that female Mlkl(-/-) mice showed delayed immune system aging and reduced age-related chronic sterile inflammation compared to wild-type mice. These findings suggest a possible application of anti-necroptotic therapy in age-related inflammation.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Multidisciplinary Sciences
Yanxiang Meng, Sarah E. Garnish, Katherine A. Davies, Katrina A. Black, Andrew P. Leis, Christopher R. Horne, Joanne M. Hildebrand, Hanadi Hoblos, Cheree Fitzgibbon, Samuel N. Young, Toby Dite, Laura F. Dagley, Aarya Venkat, Natarajan Kannan, Akiko Koide, Shohei Koide, Alisa Glukhova, Peter E. Czabotar, James M. Murphy
Summary: This study reveals the precise mechanism of the terminal steps in the necroptosis pathway, showing that phosphorylation of the MLKL activation loop by RIPK3 kinase is a key signal for MLKL pseudokinase domain dimerization, which subsequently drives the formation of elongated homotetramers of MLKL.
NATURE COMMUNICATIONS
(2023)