Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development

Abstract ABIN1 is a polyubiquitin-binding protein known to regulate NF-κB activation and cell death signaling. Mutations in Abin1 can cause severe immune diseases in human, such as psoriasis, systemic lupus erythematosus, and systemic sclerosis. Here, we generated mice that disrupted the ubiquitin-binding domain of ABIN1 (Abin1UBD/UBD) died during later embryogenesis owing to TNFR1-mediated cell death, similar to Abin1−/− mice. Abin1UBD/UBD cells were rendered sensitive to TNF-α-induced apoptosis and necroptosis as the inhibition of ABIN1UBD and A20 recruitment to the TNF-RSC complex leads to attenuated RIPK1 deubiquitination. Accordingly, the embryonic lethality of Abin1UBD/UBD mice was rescued via crossing with RIPK1 kinase-dead mice (Ripk1K45A/K45A) or the co-deletion of Ripk3 and one allele of Fadd, but not by the loss of Ripk3 or Mlkl alone. Unexpectedly, Abin1UBD/UBD mice with the co-deletion of Ripk3 and both Fadd alleles died at E14.5. This death was caused by spontaneous RIPK1 ubiquitination-dependent multiple inflammatory cytokines over production and could be rescued by the co-deletion of Ripk1 or Tnfr1 combined with Ifnar. Collectively, these data demonstrate the importance of the ABIN1 UBD domain, which mediates the ABIN1-A20 axis, at limiting RIPK1 activation-dependent cell death during embryonic development. Furthermore, our findings reveal a previously unappreciated ubiquitin pathway that regulates cleavage of ubiquitinated RIPK1 by FADD/Casp8 to suppress spontaneous IKK𝜀/TBK1 activation.

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PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation

Cell Death and Disease ◽

10.1038/s41419-021-04001-2 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Chenchen Zhou ◽

Xueli Zhang ◽

Cuiping Yang ◽

Yuan He ◽

Luo Zhang

Keyword(s):

Cell Death ◽

Kinase Inhibitor ◽

Receptor Interaction ◽

Ph Domain ◽

Tnf Α ◽

Dependent Cell ◽

Induced Apoptosis ◽

Factor Α ◽

Deficient Mice ◽

Necrosis Factor

AbstractReceptor interaction protein kinase 1 (RIPK1) plays a diverse role in tumor necrosis factor α (TNFα) signalings. The ubiquitination of RIPK1 is essential for NF-κB activation, whereas its kinase activity promotes apoptosis and necroptosis. However, the mechanisms underlying have not been fully illuminated. Here we report that PH domain-containing family O member 2 (PLEKHO2) inhibits RIPK1-dependent cell death and is necessary for NF-κB activation in response to TNFα. Cells of PLKEHO2 deficiency are more susceptible to TNF-α induced apoptosis and necroptosis with increased RIPK1 activation, which is consistent with the observation that the susceptibility of PLEKHO2−/− cells is effectively prevented by treatment of RIPK1 kinase inhibitor. Moreover, PLEKHO2 deficient cells exhibit compromised RIPK1 ubiquitination and NF-κB activation in response to TNFα. Ultimately, PLEKHO2-deficient mice display greatly increased hepatotoxicity and lethality after TNFα-induced hepatitis. In summary, our study revealed that PLEKHO2 is a novel inhibitor of apoptosis and necroptosis, which plays a key role in regulating RIPK1 ubiquitination and activation

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Faculty Opinions recommendation of The ubiquitin binding domain ZnF UBP recognizes the C-terminal diglycine motif of unanchored ubiquitin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030611.370788 ◽

2006 ◽

Author(s):

Jane Endicott

Keyword(s):

Binding Domain ◽

Ubiquitin Binding ◽

Ubiquitin Binding Domain

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Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae

Toxins ◽

10.3390/toxins13010012 ◽

2020 ◽

Vol 13 (1) ◽

pp. 12

Author(s):

Kohei Ogura ◽

Kinnosuke Yahiro ◽

Joel Moss

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Vibrio Cholerae ◽

Elongation Factor ◽

Host Cells ◽

Mitogen Activated Protein Kinase ◽

Pseudomonas Exotoxin A ◽

Tnf Α ◽

Induced Apoptosis ◽

Adp Ribosyltransferase

Pathogenic microorganisms produce various virulence factors, e.g., enzymes, cytotoxins, effectors, which trigger development of pathologies in infectious diseases. Cholera toxin (CT) produced by O1 and O139 serotypes of Vibrio cholerae (V. cholerae) is a major cytotoxin causing severe diarrhea. Cholix cytotoxin (Cholix) was identified as a novel eukaryotic elongation factor 2 (eEF2) adenosine-diphosphate (ADP)-ribosyltransferase produced mainly in non-O1/non-O139 V. cholerae. The function and role of Cholix in infectious disease caused by V. cholerae remain unknown. The crystal structure of Cholix is similar to Pseudomonas exotoxin A (PEA) which is composed of an N-terminal receptor-recognition domain and a C-terminal ADP-ribosyltransferase domain. The endocytosed Cholix catalyzes ADP-ribosylation of eEF2 in host cells and inhibits protein synthesis, resulting in cell death. In a mouse model, Cholix caused lethality with severe liver damage. In this review, we describe the mechanism underlying Cholix-induced cytotoxicity. Cholix-induced apoptosis was regulated by mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways, which dramatically enhanced tumor necrosis factor-α (TNF-α) production in human liver, as well as the amount of epithelial-like HepG2 cancer cells. In contrast, Cholix induced apoptosis in hepatocytes through a mitochondrial-dependent pathway, which was not stimulated by TNF-α. These findings suggest that sensitivity to Cholix depends on the target cell. A substantial amount of information on PEA is provided in order to compare/contrast this well-characterized mono-ADP-ribosyltransferase (mART) with Cholix.

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Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma

Blood ◽

10.1182/blood-2006-03-014209 ◽

2006 ◽

Vol 108 (5) ◽

pp. 1461-1468 ◽

Cited By ~ 58

Author(s):

Paul G. Ekert ◽

Anissa M. Jabbour ◽

Anand Manoharan ◽

Jacki E. Heraud ◽

Jai Yu ◽

...

Keyword(s):

Cell Death ◽

Family Members ◽

Pi3 Kinase ◽

Minor Role ◽

Growth And Survival ◽

Interleukin 3 ◽

Dependent Cell ◽

Induced Apoptosis ◽

A Minor ◽

Survival Signals

Growth and survival of hematopoietic cells is regulated by growth factors and cytokines, such as interleukin 3 (IL-3). When cytokine is removed, cells dependent on IL-3 kill themselves by a mechanism that is inhibited by overexpression of Bcl-2 and is likely to be mediated by proapoptotic Bcl-2 family members. Bad and Bim are 2 such BH3-only Bcl-2 family members that have been implicated as key initiators in apoptosis following growth factor withdrawal, particularly in IL-3-dependent cells. To test the role of Bad, Bim, and other proapoptotic Bcl-2 family members in IL-3 withdrawal-induced apoptosis, we generated IL-3-dependent cell lines from mice lacking the genes for Bad, Bim, Puma, both Bad and Bim, and both Bax and Bak. Surprisingly, Bad was not required for cell death following IL-3 withdrawal, suggesting changes to phosphorylation of Bad play only a minor role in apoptosis in this system. Deletion of Bim also had no effect, but cells lacking Puma survived and formed colonies when IL-3 was restored. Inhibition of the PI3 kinase pathway promoted apoptosis in the presence or absence of IL-3 and did not require Bad, Bim, or Puma, suggesting IL-3 receptor survival signals and PI3 kinase survival signals are independent.

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Tumor Necrosis Factor-α Attenuates Thyroid Hormone-Induced Apoptosis in Vascular Endothelial Cell Line XLgoo Established from Xenopus Tadpole Tails

Endocrinology ◽

10.1210/en.2007-1591 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3379-3389 ◽

Cited By ~ 12

Author(s):

Shuuji Mawaribuchi ◽

Kei Tamura ◽

Saori Okano ◽

Shutaro Takayama ◽

Yoshio Yaoita ◽

...

Keyword(s):

Cell Death ◽

Thyroid Hormone ◽

Cell Fate ◽

Thyroid Hormone Receptor ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Tnf Α ◽

Survival Signaling ◽

Induced Apoptosis ◽

Thyroid Hormone Receptor Β

Amphibian metamorphosis induced by T3 involves programmed cell death and the differentiation of various types of cells in degenerated and reconstructed tissues. However, the signaling pathway that directs the T3-dependent cell-fate determinations remains unclear. TNF-α is a pleiotropic cytokine that affects diverse cellular responses. Engagement of TNF-α with its receptor (TNFR1) causes intracellular apoptotic and/or survival signaling. To investigate TNF signaling functions during anuran metamorphosis, we first identified Xenopus laevis orthologs of TNF (xTNF)-α and its receptor. We found that xTNF-α activated nuclear factor-κB in X. laevis A6 cells through the Fas-associated death domain and receptor-interacting protein 1. Interestingly, xTNF-α mRNA in blood cells showed prominent expression at prometamorphosis during metamorphosis. Next, to elucidate the apoptotic and/or survival signaling induced by xTNF-α in an in vitro model of metamorphosis, we established a vascular endothelial cell line, XLgoo, from X. laevis tadpole tail. XLgoo cells formed actin stress fibers and elongated in response to xTNF-α. T3 induced apoptosis in these cells, but the addition of xTNF-α blocked the T3-induced apoptosis. In addition, treatment of the cells with T3 for 2 d induced the expression of thyroid hormone receptor-β and caspase-3, and this thyroid hormone receptor-β induction was drastically repressed by xTNF-α. Furthermore, in organ culture of the tail, xTNF-α significantly attenuated the tail degeneration induced by T3. These findings suggested that xTNF-α could protect vascular endothelial cells from apoptotic cell death induced by T3 during metamorphosis and thereby participate in the regulation of cell fate.

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A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain

Nature Cell Biology ◽

10.1038/s41556-019-0324-3 ◽

2019 ◽

Vol 21 (6) ◽

pp. 731-742 ◽

Cited By ~ 40

Author(s):

Apostolos Polykratis ◽

Arne Martens ◽

Remzi Onur Eren ◽

Yoshitaka Shirasaki ◽

Mai Yamagishi ◽

...

Keyword(s):

Binding Domain ◽

Ubiquitin Binding ◽

Ubiquitin Binding Domain

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CoCUN, a Novel Ubiquitin Binding Domain Identified in N4BP1

Biomolecules ◽

10.3390/biom9070284 ◽

2019 ◽

Vol 9 (7) ◽

pp. 284 ◽

Cited By ~ 5

Author(s):

Ridvan Nepravishta ◽

Federica Ferrentino ◽

Walter Mandaliti ◽

Anna Mattioni ◽

Janine Weber ◽

...

Keyword(s):

Molecular Mechanisms ◽

Structural Model ◽

Functional Characterization ◽

Binding Domain ◽

15N Nmr ◽

Protein Sequence Analysis ◽

Hydrophobic Patch ◽

Binding Domains ◽

Ubiquitin Binding ◽

Ubiquitin Binding Domain

Ubiquitin binding domains (UBDs) are modular elements that bind non-covalently to ubiquitin and act as downstream effectors and amplifiers of the ubiquitination signal. With few exceptions, UBDs recognize the hydrophobic path centered on Ile44, including residues Leu8, Ile44, His68, and Val70. A variety of different orientations, which can be attributed to specific contacts between each UBD and surface residues surrounding the hydrophobic patch, specify how each class of UBD specifically contacts ubiquitin. Here, we describe the structural model of a novel ubiquitin-binding domain that we identified in NEDD4 binding protein 1 (N4BP1). By performing protein sequence analysis, mutagenesis, and nuclear magnetic resonance (NMR) spectroscopy of the 15N isotopically labeled protein, we demonstrate that a Phe-Pro motif in N4BP1 recognizes the canonical hydrophobic patch of ubiquitin. This recognition mode resembles the molecular mechanism evolved in the coupling of ubiquitin conjugation to endoplasmic-reticulum (ER) degradation (CUE) domain family, where an invariant proline, usually following a phenylalanine, is required for ubiquitin binding. Interestingly, this novel UBD, which is not evolutionary related to CUE domains, shares a 40% identity and 47% similarity with cullin binding domain associating with NEDD8 (CUBAN), a protein module that also recognizes the ubiquitin-like NEDD8. Based on these features, we dubbed the region spanning the C-terminal 50 residues of N4BP1 the CoCUN domain, for Cousin of CUBAN. By performing circular dichroism and 15N NMR chemical shift perturbation of N4BP1 in complex with ubiquitin, we demonstrate that the CoCUN domain lacks the NEDD8 binding properties observed in CUBAN. We also show that, in addition to mediating the interaction with ubiquitin and ubiquitinated substrates, both CUBAN and CoCUN are poly-ubiquitinated in cells. The structural and the functional characterization of this novel UBD can contribute to a deeper understanding of the molecular mechanisms governing N4BP1 function, providing at the same time a valuable tool for clarifying how the discrimination between ubiquitin and the highly related NEDD8 is achieved.

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Tumor necrosis factor-α and ceramide induce cell death through different mechanisms in rat mesangial cells

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.3.f390 ◽

1999 ◽

Vol 276 (3) ◽

pp. F390-F397 ◽

Cited By ~ 2

Author(s):

Yan-Lin Guo ◽

Baobin Kang ◽

Li-Jun Yang ◽

John R. Williamson

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Mesangial Cells ◽

Tnf Α ◽

Induced Apoptosis ◽

Factor Α ◽

Necrosis Factor

It has been proposed that ceramide acts as a cellular messenger to mediate tumor necrosis factor-α (TNF-α)-induced apoptosis. Based on this hypothesis, it was postulated that resistance of some cells to TNF-α cytotoxicity was due to an insufficient production of ceramide on stimulation by TNF-α. The present study was initiated to investigate whether this was the case in mesangial cells, which normally are insensitive to TNF-α-induced apoptosis. Our results indicate that although C2ceramide was toxic to mesangial cells, the cell death it induced differed both morphologically and biochemically from that induced by TNF-α in the presence of cycloheximide (CHX). The most apparent effect of C2ceramide was to cause cells to swell, followed by disruption of the cell membrane. It is evident that C2ceramide caused cell death by necrosis, whereas TNF-α in the presence of CHX killed the cells by apoptosis. C2ceramide did not mimic the effects of TNF-α on the activation of c-Jun NH2-terminal protein kinase and nuclear factor-κB transcription factor. Although mitogen-activated protein kinase [extracellular signal-related kinase (ERK)] was activated by both C2ceramide and TNF-α, such activation appeared to be mediated by different mechanisms as judged from the kinetics of ERK activation. Furthermore, the cleavage of cytosolic phospholipase A2during cell death induced by C2ceramide and by TNF-α in the presence of CHX showed distinctive patterns. The present study provides evidence that apoptosis and necrosis use distinctive signaling machinery to cause cell death.

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TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

eLife ◽

10.7554/elife.03464 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 145

Author(s):

James A Rickard ◽

Holly Anderton ◽

Nima Etemadi ◽

Ueli Nachbur ◽

Maurice Darding ◽

...

Keyword(s):

Cell Death ◽

Transcriptional Activity ◽

Peyer's Patches ◽

Peyer’S Patches ◽

Inflammatory Phenotype ◽

Dependent Cell ◽

Perinatal Lethality ◽

Induced Apoptosis ◽

Deficient Mice

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.

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