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
Cell Biology
Giovanni Luca Beretta, Nadia Zaffaroni
Summary: Necroptosis is a cell death mechanism characterized by inflammatory reactions and is involved in viral defense, inflammatory diseases, and drug response of tumors such as prostate cancer.
Review
Biochemistry & Molecular Biology
Emma C. Tovey Crutchfield, Sarah E. Garnish, Joanne M. Hildebrand
Summary: Necroptosis is an inflammatory form of cell death evolved to defend against pathogens. Small molecules targeting RIPK1 kinase activity have shown promise in disease models, triggering significant investment in necroptosis blocking drugs. Understanding the role of MLKL in murine disease models is crucial for identifying human indications for targeted drug therapies.
Review
Biochemistry & Molecular Biology
Shanhui Liu, Kanak Joshi, Mitchell F. Denning, Jiwang Zhang
Summary: RIPK3 is a serine/threonine-protein kinase that plays key roles in inflammation and necrosis, potentially with different effects in cancer pathogenesis. It is involved in regulating various cellular processes such as apoptosis, mitochondrial metabolism, and cell proliferation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Dentistry, Oral Surgery & Medicine
Yuan Yue, Weicheng Chan, Jing Zhang, Jie Liu, Min Wang, Liang Hao, Jiajia Wang
Summary: In this study, the involvement and role of receptor-interacting protein 3 (RIP3)-mediated necroptosis in periodontitis were investigated. RIP3 phosphorylation and activation were observed in the periodontal ligament of mice infected with Porphyromonas gingivalis. Knockdown of RIP3 reduced osteoclastogenesis and inflammatory cytokines in the periodontal area, and alleviated alveolar bone loss. In vitro experiments showed that P. gingivalis-LPS induced RIP3-mediated necroptosis in fibroblast cells, and knockdown of RIP3 decreased the expression of inflammatory cytokines. These findings suggest that RIP3-mediated necroptosis plays a role in periodontitis, and targeting RIP3 may be a potential treatment approach.
Article
Multidisciplinary Sciences
Diego A. Rodriguez, Giovanni Quarato, Swantje Liedmann, Bart Tummers, Ting Zhang, Cliff Guy, Jeremy Chase Crawford, Gustavo Palacios, Stephane Pelletier, Halime Kalkavan, Jeremy J. P. Shaw, Patrick Fitzgerald, Mark J. Chen, Siddharth Balachandran, Douglas R. Green
Summary: This study identifies a molecular mechanism whereby Caspase-8 and FADD suppress spontaneous necroptotic cell death. The absence of Caspase-8 or FADD leads to the activation of RIPK3 and MLKL, resulting in necroptosis. This process relies on the nucleic acid sensor ZBP1 and its associated signaling pathways.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Yiliang Chen, Wenqing Ren, Qingsong Wang, Yuan He, Dan Ma, Zhenyu Cai
Summary: Necroptosis is a programmed necrosis mediated by specific proteins, and dysregulation of it can lead to various diseases. Recent research has shown that ubiquitylation plays a crucial role in regulating the Necroptosis signaling pathway, and exploring ubiquitylation enzymes and regulatory proteins can contribute to the development of therapeutic strategies.
Review
Genetics & Heredity
Zirui Ye, Nana Zhang, Hong Lei, Huimin Yao, Jingya Fu, Nan Zhang, Lexuan Xu, Guxiang Zhou, Zhijun Liu, Yi Lv
Summary: Necroptosis is a recently discovered mode of cell death that is distinct from necrosis and apoptosis. It plays a critical role in various biological processes and is closely associated with the occurrence and development of diseases. This article outlines the etiology of necroptosis and its impact on prevalent liver diseases, as well as reviewing therapeutic strategies targeting the necroptosis pathway. Further research is needed to understand the mechanisms governing this signaling pathway and the effector molecules.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2023)
Article
Biochemistry & Molecular Biology
Zikou Liu, Laura F. Dagley, Kristy Shield-Artin, Samuel N. Young, Aleksandra Bankovacki, Xiangyi Wang, Michelle Tang, Jason Howitt, Che A. Stafford, Ueli Nachbur, Cheree Fitzgibbon, Sarah E. Garnish, Andrew Webb, David Komander, James M. Murphy, Joanne M. Hildebrand, John Silke
Summary: MLKL undergoes multi-mono-ubiquitylation during necroptosis, accumulating in a digitonin-insoluble cell fraction. This ubiquitylated MLKL form can be reduced by expression of a deubiquitylating enzyme located on the plasma membrane, correlating with turnover. Removal of ubiquitin from MLKL induces its activation independent of necroptosis signaling, controlling basal levels to prevent unwanted cell death.
Article
Cell Biology
Huiling Zhou, Lijun Liu, Xiaolong Ma, Jian Wang, Jinfu Yang, Xinmin Zhou, Yifeng Yang, Haidan Liu
Summary: Vinblastine, a first-line anti-tumor drug, has been associated with myocardial damage, the underlying molecular mechanism of which remains unknown. This study demonstrates that necroptosis is involved in vinblastine-induced myocardial damage, and targeting necroptosis could potentially alleviate chemotherapy-related myocardial injury.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Suzette N. Palmer, Sruthi Chappidi, Chelsea Pinkham, Dustin C. Hancks
Summary: Research suggests that RIPK3 and MLKL show strong positive selection in primates and bats, possibly as a response to various pathogen-encoded inhibitors. The evolution of poxviral MLKL genes is characterized by gene replacements mediated by duplication and deletion events. MLKL protein expression is stimulated by interferons in human and mouse cells.
MOLECULAR BIOLOGY AND EVOLUTION
(2021)
Review
Medicine, Research & Experimental
Chaoning Zhan, Minchun Huang, Xiaojun Yang, Jin Hou
Summary: Research has shown that MLKL not only plays a role in necroptosis, but also regulates various diseases through its non-necroptotic functions, revealing the functional complexity and diversity of this protein.
Review
Pharmacology & Pharmacy
Lingling Wang, Ling Zhou, Yuhao Zhou, Lu Liu, Weiling Jiang, Huojun Zhang, Huiguo Liu
Summary: Apoptosis has been extensively studied as a regulated cell death mechanism, but recently necroptosis, a novel form of RCD, has gained attention. Necroptosis, mediated by RIPK3 and MLKL phosphorylation, triggers inflammation through DAMP release and is implicated in various human diseases.
FRONTIERS IN PHARMACOLOGY
(2021)
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)
Article
Environmental Sciences
Lu Peng, Yawen Wang, Bingwei Yang, Qi Qin, Erqun Song, Yang Song
Summary: In this study, a novel regulatory mechanism of PCB quinone-induced necroptosis was discovered, involving the enhancement of exosome biogenesis and secretion. Inhibition of exosome secretion led to elevated necroptotic levels, indicating the presence of a negative feedback loop between MLKL and exosome secretion. This work provides a potential new mechanism for PCBs-associated toxicity and highlights the significance of exosome-mediated signaling in human diseases.
ENVIRONMENTAL POLLUTION
(2021)