scholarly journals TAT-RHIM: a more complex issue than expected

2022 ◽  
Author(s):  
Benedikt Kolbrink ◽  
Theresa Riebeling ◽  
Nikolas K. Teiwes ◽  
Claudia Steinem ◽  
Hubert Kalbacher ◽  
...  
Keyword(s):  
Cell Death ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Murine Cytomegalovirus ◽  
Target Cells ◽  
Regulated Cell Death ◽  
Regulated Necrosis ◽  
Wide Range

Murine cytomegalovirus protein M45 contains a RIP homotypic interaction motif (RHIM) that is sufficient to confer protection of infected cells against necroptotic cell death. Mechanistically, the N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils, and interacts with the endogenous RHIM domains of receptor-interacting protein kinases (RIPK) 1, RIPK3, Z-DNA binding protein 1, and TIR domain-containing adaptor-inducing interferon-β. Remarkably, all four mammalian proteins harbouring such a RHIM domain are key components of inflammatory signalling and regulated cell death processes. Immunogenic cell death by regulated necrosis causes extensive tissue damage in a wide range of diseases, including ischemia reperfusion injury, myocardial infarction, sepsis, stroke and organ transplantation. To harness the cell death suppression properties of M45 protein in a therapeutically usable manner, we developed a synthetic peptide encompassing only the RHIM domain of M45. To trigger delivery of RHIM into target cells, we fused the transactivator protein transduction domain of human immunodeficiency virus 1 to the N-terminus of the peptide. The fused peptide could efficiently penetrate eukaryotic cells, but unexpectedly it killed all tested cancer cell lines and primary cells irrespective of species without further stimulus through a necrosis-like cell death. Typical inhibitors of different forms of regulated cell death cannot impede this process, which appears to involve a direct disruption of biomembranes. Nevertheless, our finding has potential clinical relevance; reliable induction of a necrotic form of cell death distinct from all known forms of regulated cell death may offer a novel therapeutic approach to combat resistant tumour cells.

scholarly journals The RHIM within the M45 protein from murine cytomegalovirus forms heteromeric amyloid fibrils with RIPK1 and RIPK3

2018 ◽  
Author(s):  
Chi L. L. Pham ◽  
Merryn Strange ◽  
Ailis O’ Carroll ◽  
Nirukshan Shanmugam ◽  
Emma Sierecki ◽  
...  
Keyword(s):  
Cell Death ◽  
Biological Activity ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Human Cells ◽  
Terminal Region ◽  
Murine Cytomegalovirus ◽  
Homotypic Interaction ◽  
Amyloid Assembly

AbstractThe M45 protein from murine cytomegalovirus protects infected murine cells from death by necroptosis and can protect human cells from necroptosis induced by TNFR activation, when heterologously expressed. We show that the N-terminal 90 residues of the M45 protein, which contain a RIP Homotypic Interaction Motif (RHIM), are sufficient to confer protection against TNFR-induced necroptosis. This N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils and interacts with the RHIMs of human RIPK1 and RIPK3 kinases to form heteromeric amyloid fibrils in vitro. An intact RHIM core tetrad is required for the inhibition of cell death by M45 and we show that mutation of those key tetrad residues abolishes homo- and hetero-amyloid assembly by M45 in vitro, suggesting that the amyloidogenic nature of the M45 RHIM underlies its biological activity. Our results indicate that M45 mimics the interactions made by RIPK1 with RIPK3 in forming heteromeric amyloid structures.

scholarly journals Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhao ◽  
Zineng Huang ◽  
Hongling Peng
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lipid Peroxide ◽  
Kidney Injury ◽  
Hematologic Malignancies ◽  
Regulated Cell Death ◽  
Normal Metabolism

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.

scholarly journals Posttranslational Modifications in Ferroptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xiang Wei ◽  
Xin Yi ◽  
Xue-Hai Zhu ◽  
Ding-Sheng Jiang
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Posttranslational Modifications ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Degenerative Diseases ◽  
Regulated Cell Death ◽  
Parkinson’S Diseases ◽  
Apoptosis Inducing Factor ◽  
Long Chain

Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated in many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington’s, Alzheimer’s, and Parkinson’s diseases), ischemia-reperfusion injury, and cardiovascular diseases. Previous studies have identified numerous targets involved in ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) and p53 induce while glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), and GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) have been identified to participate in ferroptosis regulation. Recent advances have also highlighted the crucial roles of posttranslational modifications (PTMs) of proteins in ferroptosis. Here, we summarize the recently discovered knowledge regarding the mechanisms underlying ferroptosis, particularly the roles of PTMs in ferroptosis regulation.

scholarly journals The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

2020 ◽  
Vol 21 (21) ◽  
pp. 7889 ◽  
Author(s):  
Tanya Ravingerová ◽  
Lucia Kindernay ◽  
Monika Barteková ◽  
Miroslav Ferko ◽  
Adriana Adameová ◽  
...  
Keyword(s):  
Cell Death ◽  
Iron Metabolism ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Physiological Role ◽  
Cellular Respiration ◽  
Protective Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Regulated Cell Death ◽  
Wide Range

Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial “conditioning”. On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as “ferroptosis”. Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of “conditioning” with a special emphasis on the novel targets for cardioprotection.

scholarly journals Ferroptosis: regulated cell death

2020 ◽  
Vol 71 (2) ◽  
pp. 99-109
Author(s):  
Ivana Čepelak ◽  
Slavica Dodig ◽  
Daniela Čepelak Dodig
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Oxygen Species ◽  
Membrane Phospholipids ◽  
Active Iron ◽  
Regulated Cell Death ◽  
Redox Active

AbstractFerroptosis is a recently identified form of regulated cell death that differs from other known forms of cell death morphologically, biochemically, and genetically. The main properties of ferroptosis are free redox-active iron and consequent iron-dependent peroxidation of polyunsaturated fatty acids in cell membrane phospholipids, which results in the accumulation of lipid-based reactive oxygen species due to loss of glutathione peroxidase 4 activity. Ferroptosis has increasingly been associated with neurodegenerative diseases, carcinogenesis, stroke, intracerebral haemorrhage, traumatic brain injury, and ischemia-reperfusion injury. It has also shown a significant therapeutic potential in the treatment of cancer and other diseases. This review summarises current knowledge about and the mechanisms that regulate ferroptosis.

scholarly journals Targeting Ferroptosis to Treat Cardiovascular Diseases: A New Continent to Be Explored

2021 ◽  
Vol 9 ◽  
Author(s):  
Fangze Huang ◽  
Ronghua Yang ◽  
Zezhou Xiao ◽  
Yu Xie ◽  
Xuefeng Lin ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiovascular Diseases ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glutamine Metabolism ◽  
Lipid Hydroperoxides ◽  
Genetic Manipulations ◽  
Regulated Cell Death ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Cardiovascular diseases, including cardiomyopathy, myocardial infarction, myocardial ischemia/reperfusion injury, heart failure, vascular injury, stroke, and arrhythmia, are correlated with cardiac and vascular cell death. Ferroptosis is a novel form of non-apoptotic regulated cell death which is characterized by an iron-driven accumulation of lethal lipid hydroperoxides. The initiation and execution of ferroptosis are under the control of several mechanisms, including iron metabolism, glutamine metabolism, and lipid peroxidation. Recently, emerging evidence has demonstrated that ferroptosis can play an essential role in the development of various cardiovascular diseases. Recent researches have shown the ferroptosis inhibitors, iron chelators, genetic manipulations, and antioxidants can alleviate myocardial injury by blocking ferroptosis pathway. In this review, we systematically described the mechanisms of ferroptosis and discussed the role of ferroptosis as a novel therapeutic strategy in the treatment of cardiovascular diseases.

scholarly journals Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease

2019 ◽  
Vol 99 (4) ◽  
pp. 1765-1817 ◽  
Author(s):  
Dominic P. Del Re ◽  
Dulguun Amgalan ◽  
Andreas Linkermann ◽  
Qinghang Liu ◽  
Richard N. Kitsis
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cell Death ◽  
Heart Disease ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Death Receptor ◽  
Immunogenic Cell Death ◽  
Important Conclusion ◽  
Regulated Cell Death

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.

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