scholarly journals The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas

2011 ◽  
Vol 192 (3) ◽  
pp. 391-399 ◽  
Author(s):  
Pauline G. Knox ◽  
Clare C. Davies ◽  
Marina Ioannou ◽  
Aristides G. Eliopoulos
Keyword(s):  
Adaptor Protein ◽  
Cd40 Ligand ◽  
Tnf Receptor ◽  
Death Domain ◽  
Apoptosis Induction ◽  
Cellular Functions ◽  
Cd40 Ligation ◽  
Interacting Protein ◽  
Regulatory Pathways ◽  
Signaling Complex

CD40, a tumor necrosis factor (TNF) receptor family member, is widely recognized for its prominent role in the antitumor immune response. The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40. Apoptosis induction requires a TRAF2-interacting CD40 motif but is initiated within a cytosolic death-inducing signaling complex after mobilization of receptor-bound TRAF2 to the cytoplasm. We demonstrate that receptor-interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing. Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it. This two-step mechanism of apoptosis induction expands our appreciation of commonalities in apoptosis regulatory pathways across the TNF receptor superfamily and provides a telling example of how TNF family receptors usurp alternative programs to fulfill distinct cellular functions.

Selective regulation by δ-PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils

2004 ◽  
Vol 287 (3) ◽  
pp. C633-C642 ◽  
Author(s):  
Laurie E. Kilpatrick ◽  
Shuang Sun ◽  
Helen M. Korchak
Keyword(s):  
Kinase Activity ◽  
Serine Phosphorylation ◽  
Integrin Signaling ◽  
Tnf Receptor ◽  
Death Domain ◽  
Negative Regulators ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Positive Regulators

TNF is implicated in the attenuation of neutrophil constitutive apoptosis during sepsis. Antiapoptotic signaling is mediated principally through the TNF receptor-1 (TNFR-1). In adherent neutrophils, when β-integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling. Previously, we identified the δ-PKC isotype and phosphatidylinositol (PI) 3-kinase as critical regulators of TNF signaling in adherent neutrophils. Both kinases associate with TNFR-1 in response to TNF and are required for TNFR-1 serine phosphorylation, NF-κB activation, and inhibition of apoptosis. The purpose of this study was to examine the role of δ-PKC and PI 3-kinase in the assembly of TNFR-1 signaling complex that regulates NF-κB activation and antiapoptotic signaling. Coimmunoprecipitation studies established that PI 3-kinase, δ-PKC, and TNFR-1 formed a signal complex in response to TNF. δ-PKC recruitment required both δ-PKC and PI 3-kinase activity, whereas PI 3-kinase recruitment was δ-PKC independent, suggesting that PI 3-kinase acts upstream of δ-PKC. An important regulatory step in control of antiapoptotic signaling is the assembly of the TNFR-1-TNFR-1-associated death domain protein (TRADD)-TNFR-associated factor 2 (TRAF2)-receptor interacting protein (RIP) complex that controls NF-κB activation. Inhibition of either δ-PKC or PI 3-kinase decreased TNF-mediated recruitment of RIP and TRAF2 to TNFR-1. In contrast, TRADD recruitment was enhanced. Thus δ-PKC and PI 3-kinase are positive regulators of TNF-mediated association of TRAF2 and RIP with TNFR-1. Conversely, these kinases are negative regulators of TRADD association. These results suggest that δ-PKC and PI 3-kinase regulate TNF antiapoptotic signaling at the level of the TNFR-1 through control of assembly of a TNFR-1-TRADD-RIP-TRAF2 complex.

scholarly journals Expression of TNF-αand Related Signaling Molecules in the Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis Patients

2006 ◽  
Vol 2006 ◽  
pp. 1-5 ◽  
Author(s):  
Sunil Kumar Raghav ◽  
Bhawna Gupta ◽  
Charu Agrawal ◽  
Ved P. Chaturvedi ◽  
Hasi R. Das
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Constitutive Expression ◽  
Tnf Receptor ◽  
Death Domain ◽  
Peripheral Blood Mononuclear ◽  
Interacting Protein ◽  
Blood Mononuclear Cells ◽  
Domain Protein

We examined the role of tumor necrosis factor (TNF-α) and its related signaling intermediates leading to apoptosis/proliferation in the peripheral blood mononuclear cells (PBMCs) of RA patients. The constitutive expression of mRNA for TNF-αreceptors (TNFR-I and TNFR-II) and the adapter molecules, such as the TNF receptor-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), receptor interacting protein (RIP), and TNF receptor-associated factor 2 (TRAF-2) were analyzed by reverse transcriptase-PCR (RT-PCR) in PBMCs from control and RA cases. PBMCs of RA patients showed a significant increase in TNF-αand TNFR-I expression as compared with that from control subjects along with significantly increased constitutive expression of TRADD, RIP, and TRAF-2 mRNA. There was a decrease in expression of FADD in RA patients, but the difference was not significant as compared to controls. These data suggested enhanced signaling by the TNFR-I-TRADD-RIP-TRAF-2 pathway and suppressed signaling by the TNFR-I-TRADD-FADD pathway in PBMCs of RA patients. However, the regulatory mechanisms for TNF-αinduced signaling may not be explained only by these pathways.

scholarly journals UXT-V1 protects cells against TNF-induced apoptosis through modulating complex II formation

2011 ◽  
Vol 22 (8) ◽  
pp. 1389-1397 ◽  
Author(s):  
Yuefeng Huang ◽  
Liang Chen ◽  
Yi Zhou ◽  
Heng Liu ◽  
Jueqing Yang ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Receptor Complex ◽  
Tnf Receptor ◽  
Death Domain ◽  
Complex Ii ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
Necrosis Factor

Proteins that directly regulate tumor necrosis factor (TNF) signaling have critical roles in determining cell death and survival. Previously we characterized ubiquitously expressed transcript (UXT)-V2 as a novel transcriptional cofactor to regulate nuclear factor-κB in the nucleus. Here we report that another splicing isoform of UXT, UXT-V1, localizes in cytoplasm and regulates TNF-induced apoptosis. UXT-V1 knockdown cells are hypersensitive to TNF-induced apoptosis. We demonstrated that UXT-V1 is a new component of TNF receptor signaling complex. We found that UXT-V1 binds to TNF receptor-associated factor 2 and prevents TNF receptor–associated death domain protein from recruiting Fas-associated protein with death domain. More importantly, UXT-V1 is a short-half-life protein, the degradation of which facilitates the formation of the apoptotic receptor complex II in response to TNF treatment. This study demonstrates that UXT-V1 is a novel regulator of TNF-induced apoptosis and sheds new light on the underlying molecular mechanism of this process.

scholarly journals Caspase-8 prevents sustained activation of NF-κB in monocytes undergoing macrophagic differentiation

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1442-1450 ◽  
Author(s):  
Cédric Rébé ◽  
Séverine Cathelin ◽  
Sophie Launay ◽  
Rodolphe Filomenko ◽  
Laurent Prévotat ◽  
...  
Keyword(s):  
Death Receptor ◽  
Adaptor Protein ◽  
Cell Types ◽  
Caspase 8 ◽  
Specific Cell ◽  
Death Domain ◽  
Blood Monocytes ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Macrophage Colony

Abstract Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-κB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-κB activity through RIP1 cleavage.

scholarly journals TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 765
Author(s):  
Eiji Yoshihara
Keyword(s):  
Glucose Homeostasis ◽  
Whole Body ◽  
Cellular Functions ◽  
Master Regulator ◽  
Independent Manner ◽  
Interacting Protein ◽  
Regulatory Pathways ◽  
Thioredoxin Interacting Protein ◽  
Important Regulator ◽  
Future Direction

Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.

scholarly journals Complexes of Human Papillomavirus Type 16 E6 Proteins Form Pseudo-Death-Inducing Signaling Complex Structures during Tumor Necrosis Factor-Mediated Apoptosis

2008 ◽  
Vol 83 (1) ◽  
pp. 210-227 ◽  
Author(s):  
Maria Filippova ◽  
Valery A. Filippov ◽  
Mercy Kagoda ◽  
Theodore Garnett ◽  
Nadya Fodor ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Complex Structure ◽  
Adaptor Protein ◽  
Full Length ◽  
Death Domain ◽  
Hpv16 E6 ◽  
Signaling Complex ◽  
Necrosis Factor

ABSTRACT High-risk strains of human papillomavirus (HPV) such as HPV type 16 (HPV16) and HPV18 are causative agents of most human cervical carcinomas. E6, one of the oncogenes encoded by HPV16, possesses a number of biological and transforming functions. We have previously shown that the binding of E6 to host apoptotic proteins such as tumor necrosis factor (TNF) R1, the adaptor protein FADD, and procaspase 8 results in a significant modification of the normal flow of apoptotic events. For example, E6 can bind to and accelerate the degradation of FADD. In addition, full-length E6 binds to the TNF R1 death domain and can also bind to and accelerate the degradation of procaspase 8. In contrast, the binding of small splice isoforms known as E6* results in the stabilization of procaspase 8. In this report, we propose a model for the ability of HPV16 E6 to both sensitize and protect cells from TNF as well as to protect cells from Fas. We demonstrate that both the level of E6 expression and the ratio between full-length E6 and E6* are important factors in the modification of the host extrinsic apoptotic pathways and show that at high levels of E6 expression, the further sensitization of U2OS, NOK, and Ca Ski cells to TNF-mediated apoptosis is most likely due to the formation of a pseudo-death-inducing signaling complex structure that includes complexes of E6 proteins.

scholarly journals The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

2001 ◽  
Vol 21 (12) ◽  
pp. 3986-3994 ◽  
Author(s):  
Anne Devin ◽  
Yong Lin ◽  
Shoji Yamaoka ◽  
Zhiwei Li ◽  
Michael Karin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Death Domain ◽  
Iκb Kinase ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

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.

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