scholarly journals ­­LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation

2016 ◽  
Vol 213 (12) ◽  
pp. 2671-2689 ◽  
Author(s):  
Julia Zinngrebe ◽  
Eva Rieser ◽  
Lucia Taraborrelli ◽  
Nieves Peltzer ◽  
Torsten Hartwig ◽  
...  
Keyword(s):  
Cell Death ◽  
Influenza A ◽  
Gene Activation ◽  
Ubiquitin Chain ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Biochemical Level ◽  
Chronic Proliferative Dermatitis ◽  
Tlr3 Signaling

The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1–interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.

scholarly journals Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment

2009 ◽  
Vol 187 (7) ◽  
pp. 1037-1054 ◽  
Author(s):  
Peter Geserick ◽  
Mike Hupe ◽  
Maryline Moulin ◽  
W. Wei-Lynn Wong ◽  
Maria Feoktistova ◽  
...  
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Physiological Role ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Complex Ii ◽  
Signaling Complex ◽  
Iap Antagonist ◽  
Cellular Inhibitors

A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist–induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA–mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIPL and not cFLIPS interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor–mediated cell death.

scholarly journals Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

2021 ◽  
Vol 22 (5) ◽  
pp. 2754
Author(s):  
Naila Qayyum ◽  
Muhammad Haseeb ◽  
Moon Suk Kim ◽  
Sangdun Choi
Keyword(s):  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Signaling Complex ◽  
Current Review ◽  
Wide Range ◽  
Range Of Functions ◽  
Species Production ◽  
And Oxidative Stress ◽  
Significant Attention

Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.

scholarly journals Molecular Events Involved in Influenza A Virus-Induced Cell Death

2022 ◽  
Vol 12 ◽  
Author(s):  
Rui Gui ◽  
Quanjiao Chen
Keyword(s):  
Cell Death ◽  
Influenza A Virus ◽  
Influenza A ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Tissue Destruction ◽  
Inflammatory Reactions ◽  
Molecular Events ◽  
Host Death

Viral infection usually leads to cell death. Moderate cell death is a protective innate immune response. By contrast, excessive, uncontrolled cell death causes tissue destruction, cytokine storm, or even host death. Thus, the struggle between the host and virus determines whether the host survives. Influenza A virus (IAV) infection in humans can lead to unbridled hyper-inflammatory reactions and cause serious illnesses and even death. A full understanding of the molecular mechanisms and regulatory networks through which IAVs induce cell death could facilitate the development of more effective antiviral treatments. In this review, we discuss current progress in research on cell death induced by IAV infection and evaluate the role of cell death in IAV replication and disease prognosis.

scholarly journals Polymerase Acidic Subunit of H9N2 Polymerase Complex Induces Cell Apoptosis by Binding to PDCD 7 in A549 Cells

2020 ◽  
Author(s):  
Shaohua Wang ◽  
Na Li ◽  
Shugang Jin ◽  
Ruihua Zhang ◽  
Tong Xu
Keyword(s):  
Cell Death ◽  
Influenza Virus ◽  
Cell Apoptosis ◽  
Influenza A ◽  
A549 Cells ◽  
Influenza Virus Infection ◽  
Economic Loss ◽  
Poultry Production ◽  
H9n2 Influenza Virus

Abstract Background: H9N2 influenza virus, a subtype of influenza A virus, can spread across different species and induce the respiratory infectious disease in humans, leading to a severe public health risk and a huge economic loss to poultry production. Increasing studies have shown that polymerase acidic (PA) subunit of RNA polymerase in ribonucleoproteins complex of H9N2 involves in crossing the host species barriers, the replication and airborne transmission of H9N2.Methods: Here, to further investigate the role of PA subunit during the infection of H9N2 influenza virus, we employed mass spectrometry (MS) to search the potential binding proteins of PA subunit of H9N2. Our MS results showed that programmed cell death protein 7 (PDCD7) is a binding target of PA subunit. Co-immunoprecipitation and pull-down assays further confirmed the interaction between PDCD7 and PA subunit. Overexpression of PA subunit in A549 lung cells greatly increased the levels of PDCD7 in the nuclear and induced cell death assayed by MTT assay.Results: Flow cytometry analysis and Western blot results showed that PA subunit overexpression significantly increased the expression of pro-apoptotic protein, bax and caspase 3, and induced cell apoptosis. However, knockout of PDCD7 effectively attenuated the effects of PA overexpression in cell apoptosis.Conclusions: In conclusion, the PA subunit of H9N2 bind with PDCD7 and regulated cell apoptosis, which provide new insights in the role of PA subunit during H9N2 influenza virus infection.

scholarly journals SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Grant R. Campbell ◽  
Rachel K. To ◽  
Gang Zhang ◽  
Stephen A. Spector
Keyword(s):  
Cell Death ◽  
Hiv Infection ◽  
Cell Survival ◽  
Acute Hiv Infection ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Hiv Eradication ◽  
Smac Mimetics ◽  
Smac Mimetic ◽  
Latent Hiv

Abstract Human immunodeficiency type 1 (HIV)-infected macrophages (HIV-Mφ) are a reservoir for latent HIV infection and a barrier to HIV eradication. In contrast to CD4+ T cells, HIV-Mφ are resistant to the cytopathic effects of acute HIV infection and have increased expression of cell survival factors, including X-linked inhibitor of apoptosis (XIAP), baculoviral IAP repeat containing (BIRC) 2/cIAP1, beclin-1, BCL2, BCL-xl, triggering receptor expressed on myeloid cells 1, mitofusin (MFN) 1, and MFN2. DIABLO/SMAC mimetics are therapeutic agents that affect cancer cell survival and induce cell death. We found that DIABLO/SMAC mimetics (LCL-161, AT-406 (also known as SM-406 or Debio 1143), and birinapant) selectively kill HIV-Mφ without increasing bystander cell death. DIABLO/SMAC mimetic treatment of HIV-Mφ-induced XIAP and BIRC2 degradation, leading to the induction of autophagy and the formation of a death-inducing signaling complex on phagophore membranes that includes both pro-apoptotic or necroptotic (FADD, receptor-interacting protein kinase (RIPK) 1, RIPK3, caspase 8, and MLKL) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacologic inhibition of early stages of autophagy, but not late stages of autophagy, ablated this interaction and inhibited apoptosis. Furthermore, DIABLO/SMAC mimetic-mediated apoptosis of HIV-Mφ is dependent upon tumor necrosis factor signaling. Our findings thus demonstrate that DIABLO/SMAC mimetics selectively induce autophagy-dependent apoptosis in HIV-Mφ.

scholarly journals Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death

2020 ◽  
Author(s):  
Matthias Kist ◽  
László G. Kőműves ◽  
Tatiana Goncharov ◽  
Debra L. Dugger ◽  
Charles Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Embryonic Lethality ◽  
Mapk Activation ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Ubiquitination Site ◽  
Lysine Residues ◽  
The Stability

Abstract Receptor-interacting protein 1 (RIP1; RIPK1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. TNF-TNFR1 triggered signaling complex formation, subsequent NF-κB and MAPK activation and induction of cell death involve RIPK1 ubiquitination at several lysine residues including Lys376 and Lys115. Here we show that mutating the ubiquitination site K376 of RIPK1 (K376R) in mice activates cell death resulting in embryonic lethality. In contrast to Ripk1K376R/K376R mice, Ripk1K115R/K115R mice reached adulthood and showed slightly higher responsiveness to TNF-induced death. Cell death observed in Ripk1K376R/K376R embryos relied on RIPK1 kinase activity as administration of RIPK1 inhibitor GNE684 to pregnant heterozygous mice effectively blocked cell death and prolonged survival. Embryonic lethality of Ripk1K376R/K376R mice was prevented by the loss of TNFR1, or by simultaneous deletion of caspase-8 and RIPK3. Interestingly, elimination of the wild-type allele from adult Ripk1K376R/cko mice was tolerated. However, adult Ripk1K376R/cko mice were exquisitely sensitive to TNF-induced hypothermia and associated lethality. Absence of the K376 ubiquitination site diminished K11-linked, K63-linked, and linear ubiquitination of RIPK1, and promoted the assembly of death-inducing cellular complexes, suggesting that multiple ubiquitin linkages contribute to the stability of the RIPK1 signaling complex that stimulates NF-κB and MAPK activation. In contrast, mutating K115 did not affect RIPK1 ubiquitination or TNF stimulated NF-κB and MAPK signaling. Overall, our data indicate that selective impairment of RIPK1 ubiquitination can lower the threshold for RIPK1 activation by TNF resulting in cell death and embryonic lethality.

scholarly journals The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

2020 ◽  
Vol 295 (24) ◽  
pp. 8325-8330 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R. K. Subbarao Malireddi ◽  
Amanda R. Burton ◽  
Shaina N. Porter ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Defense Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

scholarly journals Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

2016 ◽  
Vol 36 (10) ◽  
pp. 1569-1583 ◽  
Author(s):  
Satoshi Shimizu ◽  
Hiroaki Fujita ◽  
Yoshiteru Sasaki ◽  
Tatsuaki Tsuruyama ◽  
Kazuhiko Fukuda ◽  
...  
Keyword(s):  
Cell Death ◽  
Zinc Finger ◽  
Knockout Mice ◽  
Binding Activity ◽  
Effective Protection ◽  
Ubiquitin Chain ◽  
Differential Involvement ◽  
Characteristic Features ◽  
Chronic Proliferative Dermatitis ◽  
Inflammatory Phenotypes

The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB activation and cell death protection. Loss of any of the three LUBAC subunits (catalytic HOIP, accessory HOIL-1L, or accessory SHARPIN subunit) leads to distinct phenotypes in mice and human. cpdm mice (chronic proliferative dermatitis in mice [cpdm]) that lack SHARPIN exhibit chronic inflammatory phenotypes, whereas HOIL-1L knockout mice exhibit no overt phenotypes, despite sharing highly homologous ubiquitin-like (UBL) and Npl4 zinc finger (NZF) domains. Here, we intercrossed mice lacking HOIL-1L and SHARPIN and found that reduction of HOIL-1L in cpdm mice exacerbated inflammatory phenotypes without affecting characteristic features of cpdm disease, whereas reduction of SHARPIN in HOIL-1L knockout mice provoked no overt phenotypes. Hence, loss of SHARPIN and reduction of LUBAC triggers cpdm phenotypes. We found that the NZF domain of SHARPIN, but not that of HOIL-1L, is critical for effective protection from programmed cell death by enhancing the recruitment of LUBAC to the activated TNFR complex. The binding activity to K63-linked ubiquitin chains that the NZF domain of SHARPIN, but not that of HOIL-1L, possesses appears to be involved in the recruitment. Thus, selective recognition of ubiquitin chains by NZFs in LUBAC underlies the regulation of LUBAC function.

scholarly journals Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death

2020 ◽  
Author(s):  
Rosalind L. Ang ◽  
John P. Sundberg ◽  
Shao-Cong Sun ◽  
Virginia L. Gillespie ◽  
Peter S. Heeger ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Dysregulation ◽  
Ubiquitin Chain ◽  
Physiological Conditions ◽  
Signaling Complex ◽  
Conditional Deletion ◽  
Short Summary ◽  
Dependent Inhibition ◽  
Dependent Cell ◽  
Deficient Mice

AbstractSHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked poly-ubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to auto-inflammation and immunodeficiency but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpin-/- mice is dependent on CYLD, the deubiquitinase that removes K63-linked poly-ubiquitin chains. The dermatitis, disrupted splenic architecture, and loss of Peyer’s patches in the Sharpin-/- mice were fully reversed in Sharpin-/-Cyld-/- mice. There is enhanced association of RIPK1 with the death-inducing signaling complex (DISC) following TNF stimulation in Sharpin-/- cells, and this is dependent on CYLD since it is reversed in Sharpin-/-Cyld-/- cells. Enhanced RIPK1 recruitment to the DISC in Sharpin-/- cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpin-/- mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpin-/- phenotype illustrates the pathological consequences when CYLD inhibition fails.Short SummaryIn the absence of SHARPIN, cells fail to properly regulate the deubiquitinase CYLD, leading to RIPK1-mediated cell death. Deletion of Cyld reverses the sensitivity of Sharpin-/- cells to TNF-induced cell death, as well as the multi-organ inflammation and immune dysfunction observed in Sharpin-/- mice.

scholarly journals The Vps27/Hrs/STAM (VHS) Domain of the Signal-transducing Adaptor Molecule (STAM) Directs Associated Molecule with the SH3 Domain of STAM (AMSH) Specificity to Longer Ubiquitin Chains and Dictates the Position of Cleavage

2015 ◽  
Vol 291 (4) ◽  
pp. 2033-2042 ◽  
Author(s):  
Nardeen Baiady ◽  
Prasanth Padala ◽  
Bayan Mashahreh ◽  
Einav Cohen-Kfir ◽  
Emily A. Todd ◽  
...  
Keyword(s):  
Structural Model ◽  
Sh3 Domain ◽  
Deubiquitinating Enzyme ◽  
Cleavage Rate ◽  
Ubiquitin Chain ◽  
Interacting Protein ◽  
Chain Cleavage ◽  
Substrate Cleavage ◽  
Vhs Domain

The deubiquitinating enzyme associated molecule with the SH3 domain of STAM (AMSH) is crucial for the removal of ubiquitin molecules during receptor-mediated endocytosis and lysosomal receptor sorting. AMSH interacts with signal transducing adapter molecule (STAM) 1 or 2, which enhances the activity of AMSH through an unknown mechanism. This stimulation is dependent on the ubiquitin-interacting motif of STAM. Here we investigate the specific mechanism of AMSH stimulation by STAM proteins and the role of the STAM Vps27/Hrs/STAM domain. We show that, in the presence of STAM, the length of the ubiquitin chains affects the apparent cleavage rate. Through measurement of the chain cleavage kinetics, we found that, although the kcat of Lys63-linked ubiquitin chain cleavage was comparable for di- and tri-ubiquitin, the Km value was lower for tri-ubiquitin. This increased affinity for longer chains was dependent on the Vps27/Hrs/STAM domain of STAM and required that the substrate ubiquitin chain contain homogenous Lys63-linkages. In addition, STAM directed AMSH cleavage toward the distal isopeptide bond in tri-ubiquitin chains. Finally, we generated a structural model of AMSH-STAM to show how the complex binds Lys63-linked ubiquitin chains and cleaves at the distal end. These data show how a deubiquitinating enzyme-interacting protein dictates the efficiency and specificity of substrate cleavage.

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