Deubiquitinases: Modulators of Different Types of Regulated Cell Death

The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽

10.3390/cancers13184576 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4576

Author(s):

Hung-Yu Lin ◽

Hui-Wen Ho ◽

Yen-Hsiang Chang ◽

Chun-Jui Wei ◽

Pei-Yi Chu

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Drug Resistant ◽

Therapeutic Targeting ◽

The Past ◽

Regulated Cell Death ◽

Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

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Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

Nature Communications ◽

10.1038/s41467-020-20806-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joanna L. Fox ◽

Michelle A. Hughes ◽

Xin Meng ◽

Nikola A. Sarnowska ◽

Ian R. Powley ◽

...

Keyword(s):

Cell Death ◽

Structural Analysis ◽

Cell Fate ◽

Catalytic Domain ◽

Caspase 8 ◽

Type I ◽

Signaling Complex ◽

Catalytic Domains ◽

Regulated Cell Death ◽

Death Effector

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

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The multi-faceted functioning portrait of LRF/ZBTB7A

Human Genomics ◽

10.1186/s40246-019-0252-0 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Caterina Constantinou ◽

Magda Spella ◽

Vasiliki Chondrou ◽

George P. Patrinos ◽

Adamantia Papachatzopoulou ◽

...

Keyword(s):

Cell Fate ◽

Cellular Response ◽

Molecular Mechanisms ◽

Aerobic Glycolysis ◽

Specific Cell ◽

Regulation Of Transcription ◽

Cancer Type ◽

Cellular Effects ◽

Physiological Processes ◽

Signaling Axis

AbstractTranscription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A’s orchestrated action.

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Comprehensive Map of the Regulated Cell Death Signaling Network: A Powerful Analytical Tool for Studying Diseases

Cancers ◽

10.3390/cancers12040990 ◽

2020 ◽

Vol 12 (4) ◽

pp. 990

Author(s):

Jean-Marie Ravel ◽

L. Cristobal Monraz Gomez ◽

Nicolas Sompairac ◽

Laurence Calzone ◽

Boris Zhivotovsky ◽

...

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Signaling Network ◽

Tumor Subtypes ◽

Navigation Data ◽

Manual Curation ◽

Regulated Cell Death ◽

Powerful Analytical Tool ◽

Cell Death Signaling ◽

The Difference

The processes leading to, or avoiding cell death are widely studied, because of their frequent perturbation in various diseases. Cell death occurs in three highly interconnected steps: Initiation, signaling and execution. We used a systems biology approach to gather information about all known modes of regulated cell death (RCD). Based on the experimental data retrieved from literature by manual curation, we graphically depicted the biological processes involved in RCD in the form of a seamless comprehensive signaling network map. The molecular mechanisms of each RCD mode are represented in detail. The RCD network map is divided into 26 functional modules that can be visualized contextually in the whole seamless network, as well as in individual diagrams. The resource is freely available and accessible via several web platforms for map navigation, data integration, and analysis. The RCD network map was employed for interpreting the functional differences in cell death regulation between Alzheimer’s disease and non-small cell lung cancer based on gene expression data that allowed emphasizing the molecular mechanisms underlying the inverse comorbidity between the two pathologies. In addition, the map was used for the analysis of genomic and transcriptomic data from ovarian cancer patients that provided RCD map-based signatures of four distinct tumor subtypes and highlighted the difference in regulations of cell death molecular mechanisms.

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Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

Frontiers in Oncology ◽

10.3389/fonc.2021.743006 ◽

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.

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Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

Microorganisms ◽

10.3390/microorganisms9102152 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2152

Author(s):

Brittany Friedson ◽

Katrina F. Cooper

Keyword(s):

Cell Death ◽

Rna Polymerase Ii ◽

Cell Fate ◽

Ubiquitin Proteasome System ◽

Mitochondrial Morphology ◽

Atp Production ◽

Cell Fate Decisions ◽

Regulated Cell Death ◽

Cyclin C ◽

Convergence Point

The Cdk8 kinase module (CKM) of the multi-subunit mediator complex plays an essential role in cell fate decisions in response to different environmental cues. In the budding yeast S. cerevisiae, the CKM consists of four conserved subunits (cyclin C and its cognate cyclin-dependent kinase Cdk8, Med13, and Med12) and predominantly negatively regulates a subset of stress responsive genes (SRG’s). Derepression of these SRG’s is accomplished by disassociating the CKM from the mediator, thus allowing RNA polymerase II-directed transcription. In response to cell death stimuli, cyclin C translocates to the mitochondria where it induces mitochondrial hyper-fission and promotes regulated cell death (RCD). The nuclear release of cyclin C requires Med13 destruction by the ubiquitin-proteasome system (UPS). In contrast, to protect the cell from RCD following SRG induction induced by nutrient deprivation, cyclin C is rapidly destroyed by the UPS before it reaches the cytoplasm. This enables a survival response by two mechanisms: increased ATP production by retaining reticular mitochondrial morphology and relieving CKM-mediated repression on autophagy genes. Intriguingly, nitrogen starvation also stimulates Med13 destruction but through a different mechanism. Rather than destruction via the UPS, Med13 proteolysis occurs in the vacuole (yeast lysosome) via a newly identified Snx4-assisted autophagy pathway. Taken together, these findings reveal that the CKM regulates cell fate decisions by both transcriptional and non-transcriptional mechanisms, placing it at a convergence point between cell death and cell survival pathways.

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Pterin-based pigmentation in animals

Biology Letters ◽

10.1098/rsbl.2021.0221 ◽

2021 ◽

Vol 17 (8) ◽

pp. 20210221

Author(s):

Pedro Andrade ◽

Miguel Carneiro

Keyword(s):

Molecular Mechanisms ◽

Potential Model ◽

Honest Signalling ◽

Functional Studies ◽

Physiological Processes ◽

History Of Research ◽

Different Types ◽

Genomic Studies ◽

History Of ◽

Advance Research

Pterins are one of the major sources of bright coloration in animals. They are produced endogenously, participate in vital physiological processes and serve a variety of signalling functions. Despite their ubiquity in nature, pterin-based pigmentation has received little attention when compared to other major pigment classes. Here, we summarize major aspects relating to pterin pigmentation in animals, from its long history of research to recent genomic studies on the molecular mechanisms underlying its evolution. We argue that pterins have intermediate characteristics (endogenously produced, typically bright) between two well-studied pigment types, melanins (endogenously produced, typically cryptic) and carotenoids (dietary uptake, typically bright), providing unique opportunities to address general questions about the biology of coloration, from the mechanisms that determine how different types of pigmentation evolve to discussions on honest signalling hypotheses. Crucial gaps persist in our knowledge on the molecular basis underlying the production and deposition of pterins. We thus highlight the need for functional studies on systems amenable for laboratory manipulation, but also on systems that exhibit natural variation in pterin pigmentation. The wealth of potential model species, coupled with recent technological and analytical advances, make this a promising time to advance research on pterin-based pigmentation in animals.

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Abstract 333: Cardiomyocyte Death and Fibrotic Scarring in the Infarcted Neonatal Mouse Heart

Circulation Research ◽

10.1161/res.127.suppl_1.333 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Mary Mohr ◽

Ge Tao ◽

Shuang Li ◽

Patrick Roddy

Keyword(s):

Cell Death ◽

The United States ◽

Artery Occlusion ◽

Scar Formation ◽

Mouse Heart ◽

Public Health Burden ◽

Regulated Cell Death ◽

Different Types ◽

Neonatal Cardiomyocyte

As one the leading causes of death in the United States, myocardial infarction (MI) occurs every 40 seconds, causing severe public health burden. Following MI, the loss of healthy cardiomyocytes leads to decreased contractility and eventually heart failure. Mature mammalian cardiomyocytes have a low turnover rate at only 0.5-2% per year, insufficient for repopulating damaged myocardium after MI. However, a contradictory discovery was made showing that the neonatal mammalian heart is regenerative, although this reparative ability is lost within days after birth. A great amount of effort is needed to understand the mechanisms underlying neonatal cardiomyocyte regeneration. In the current project, we attempt to profile different types of cell death in regenerating and non-regenerating mouse models following MI, in order to gain insights into a favorable type of cardiomyocyte death during regeneration. We induced MI in postnatal day 1 (P1, regenerative), and postnatal day 7 (P7, non-regenerative) mouse hearts by left anterior descending artery occlusion (LAD-O). The progressive scar formation was assessed using Masson’s Trichrome staining at multiple timepoints up to 14 days after MI. At each time point, we profile three major types of regulated cell death, apoptosis, necroptosis, and ferroptosis, using immunofluorescence staining. We also used AC16, a human cardiomyocyte cell line, to investigate the role of cell density in the regulation of ferroptosis. We found that the scar formation was most dynamic between 2 and 3 days after MI and that the course of scar formation varied greatly between P1 and P7 hearts. Immunofluorescence of different cell death markers reveal differentially progressed cell death between P1 and P7 hearts after MI. Our results indicate a different pattern of cardiomyocyte death in the regenerative P1 heart compared to the non-regenerative P7 heart, that could be more favorable for myocardial regeneration.

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Insights into neural stem cell biology from flies

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2006.2011 ◽

2007 ◽

Vol 363 (1489) ◽

pp. 39-56 ◽

Cited By ~ 92

Author(s):

Boris Egger ◽

James M Chell ◽

Andrea H Brand

Keyword(s):

Stem Cell ◽

Cell Fate ◽

Neural Stem Cell ◽

Cell Biology ◽

Molecular Mechanisms ◽

Neurological Injury ◽

Temporal Regulation ◽

Stem Cell Maintenance ◽

Different Types ◽

Made In

Drosophila neuroblasts are similar to mammalian neural stem cells in their ability to self-renew and to produce many different types of neurons and glial cells. In the past two decades, great advances have been made in understanding the molecular mechanisms underlying embryonic neuroblast formation, the establishment of cell polarity and the temporal regulation of cell fate. It is now a challenge to connect, at the molecular level, the different cell biological events underlying the transition from neural stem cell maintenance to differentiation. Progress has also been made in understanding the later stages of development, when neuroblasts become mitotically inactive, or quiescent, and are then reactivated postembryonically to generate the neurons that make up the adult nervous system. The ability to manipulate the steps leading from quiescence to proliferation and from proliferation to differentiation will have a major impact on the treatment of neurological injury and neurodegenerative disease.

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Programmed Cell Death in the Pathogenesis of Influenza

International Journal of Molecular Sciences ◽

10.3390/ijms19072065 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2065 ◽

Cited By ~ 18

Author(s):

Daisuke Fujikura ◽

Tadaaki Miyazaki

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Molecular Mechanisms ◽

Immune Reaction ◽

Experimental Studies ◽

Economic Costs ◽

Organ Function ◽

Virus Propagation ◽

Public Health Systems ◽

Different Types

Influenza is a respiratory disease induced by infection by the influenza virus, which is a member of Orthomyxoviridae family. This infectious disease has serious impacts on public health systems and results in considerable mortality and economic costs throughout the world. Based on several experimental studies, massive host immune reaction is associated with the disease severity of influenza. Programmed cell death is typically induced during virus infection as a consequence of host immune reaction to limit virus spread by eliminating niches for virus propagation without causing inflammation. However, in some viral infectious diseases, such as influenza, in the process of immune reaction, aberrant induction of programmed cell death disturbs the maintenance of organ function. Current reports show that there are different types of programmed cell death that vary in terms of molecular mechanisms and/or associations with inflammation. In addition, these novel types of programmed cell death are associated with pathogenesis rather than suppressing virus propagation in the disease course. Here, we review our current understanding of mechanisms of programmed cell death in the pathogenesis of influenza.

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