The Mouse Cell Surface Protein TOSO Regulates Fas/Fas Ligand-induced Apoptosis through Its Binding to Fas-associated Death Domain

Song, Yahui; Jacob, Chaim O.

doi:10.1074/jbc.m413609200

Cited by 35 publications

(26 citation statements)

References 32 publications

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“…Together with the antiapoptotic effects of Toso in type I and type II cells, these data suggest that Toso generally exhibits a protective function on death receptor-mediated forms of cell death. In addition, unlike earlier reports on type II Jurkat cells, 10,19 we observed no significant increase in caspase-8 cleavage in BJAB (type I) Toso knock-down cells, although these cells exhibit enhanced apoptosis on CD95 stimulation compared with control cells (supplemental Figure 4C). Together, our results indicate that Toso exhibits its antiapoptotic function by acting on signaling events that either lie downstream or in parallel to the activation of initiator caspase-8.…”

Section: Toso Is a Novel Negative Regulator For Cd95-induced Apoptosiscontrasting

confidence: 99%

“…This observation extends previous reports describing an interaction between the death domain of RIP1 and FADD, 29 and an in vitro interaction between FADD and the C-terminus of Toso. 19 While Toso and RIP1 interact constitutively with each other, the association of FADD with the complex is stabilized by CD95-stimulation. Furthermore, our studies using the RIP1-K377R ubiquitination mutant indicate that efficient recruitment of FADD also depends on RIP1 ubiquitination.…”

Section: Toso Facilitates Rip1 Ubiquitinationmentioning

confidence: 99%

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Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination

Nguyen

Lang

et al. 2011

Blood

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The regulation of cellular survival and apoptosis is of critical importance for the immune system to maintain immune homeostasis and to establish tolerance. Here, we demonstrate that the immune specific cell surface molecule Toso exhibits antiapoptotic effects on death receptor signaling by a novel regulatory mechanism involving the adaptor kinase RIP1.The antiapoptotic function of Toso depends on RIP1 ubiquitination and involves the recruitment of the death adaptor FADD to a Toso/RIP1 protein complex. In response to CD95L and TNF␣, Toso promotes the activation of MAPK and NF-B signaling pathways. Because of this relative augmentation of survival versus apoptotic signals, Toso raises the threshold for death receptormediated apoptosis. Our analysis of Tosodeficient mice revealed that Toso is essential for TNF␣-mediated liver damage. Furthermore, the antiapoptotic function of Toso could be blocked by a Toso-specific monoclonal antibody, opening up new therapeutic prospects for the treatment of immune disorders and hematologic malignancies. (Blood. 2011;118(3):598-608) IntroductionOne of the most well-characterized death receptors in the immune system is CD95 (Fas, APO-1). CD95 belongs to the TNF receptor superfamily. Expressed as preassociated homotrimers, CD95 on ligand binding directly conveys apoptotic signals. On ligand binding, CD95 assembles the death inducing signaling complex (DISC). The DISC consists of the death adaptor FADD (Fas associated death domain protein), procaspase-8, and procaspase-10. 1,2 Efficient DISC formation provides a molecular scaffold concentrating cysteine proteases to induce autoproteolytic cleavage of caspase-8 and release of active caspase-8 that initiates the apoptotic program. Mutations of CD95 or its ligand have been found in autoimmune strains of mice and in patients with autoimmune lymphoproliferative syndrome (ALPS). 3 These genetic abnormalities in CD95 result in the development of massive lymphoadenopathy and disruption of lymphocyte homeostasis because of increased survival of activated lymphocytes. 4,5 Although CD95 has been mainly perceived as a death inducing receptor, recent findings paint a far more complex picture of CD95 and the DISC components by providing evidence that they can transmit both, deathinducing and cellular activation signals in response to the same ligand. 6,7 Such nonapoptotic signaling activities of CD95 are thought to mediate proinflammatory responses in immune cells, neuronal tissue remodeling and promote tumor progression. [7][8][9] The execution and regulation of CD95-mediated nonapoptotic signaling, in particular with respect to its contribution to tumorigenesis, is however still largely unclear.Toso, also known as FAIM3, is a type I transmembrane protein belonging to the immunoglobulin gene superfamily. Toso was originally identified as a surface molecule with negative regulatory function on lymphocyte apoptosis. 10 Recent studies have also implicated Toso in IgM binding. 11 The expression of Toso is restricted to lymphoid organs, where it is ...

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Section: Toso Is a Novel Negative Regulator For Cd95-induced Apoptosiscontrasting

confidence: 99%

Section: Toso Facilitates Rip1 Ubiquitinationmentioning

confidence: 99%

Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination

Nguyen

Lang

et al. 2011

Blood

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“…In Jurkat cells stably transfected with TOSO, it was demonstrated that Fas-induced activation of caspase-8 was significantly inhibited by the expression of TOSO. 9 In addition to that, it was shown in CLL cells that PI3-kinase enables their survival by preventing caspase-8 activation. 14 Furthermore, recent results suggest that caspase-8 processing is inhibited by TOSO through up-regulation of cFLIP.…”

Section: Discussionmentioning

confidence: 96%

“…Besides protection of CLL cells from Fas-induced apoptosis, it was also elucidated that TOSO counteracts TNF-induced apoptosis. 9 In CLL cells, 2 related members of the TNF family, that is, BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand) were shown to be overexpressed and involved in resistance to apoptosis through an autocrine pathway. 15 In our experiments, we could demonstrate that CLL cells down-regulate TOSO after being stimulated via their CD40 receptor by CD40L.…”

Section: Discussionmentioning

confidence: 99%

“…8 In a murine model, inhibition of Fas-mediated apoptosis was shown to be mediated by binding of the C-terminal domain of TOSO with FADD. 9 Nevertheless, the function of the transmembrane-protein TOSO has not yet been fully described, therefore neither a ligand of the TOSO extracellular domain nor regulatory mechanisms of TOSO expression could be identified.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Pallasch¹,

Schulz²,

Kutsch³

et al. 2008

Blood

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Indications for cell stress in response to adenoviral and baculoviral gene transfer observed by proteome profiling of human cancer cells

et al. 2010

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Gene transfer to cultured cells is an important tool for functional studies in many areas of biomedical research and vector systems derived from adenoviruses and baculoviruses are frequently used for this purpose. In order to characterize how viral gene transfer vectors affect the functional state of transduced cells, we applied 2-D PAGE allowing quantitative determination of protein amounts and synthesis rates of metabolically labeled cells and shotgun proteomics. Using HepG2 human hepatoma cells we show that both vector types can achieve efficient expression of green fluorescent protein, which accounted for about 0.1% of total cellular protein synthesis 72 h after transduction. No evidence in contrast was found for expression of proteins from the viral backbones. With respect to the host cell response, both vectors induced a general increase in protein synthesis of about 50%, which was independent of green fluorescent protein expression. 2-D PAGE autoradiographs identified a 3.6-fold increase of gamma-actin synthesis in adenovirus transduced cells. In addition shotgun proteomics of cytoplasmic and nuclear extract fractions identified a slight induction of several proteins related to inflammatory activation, cell survival and chromatin function by both virus types. These data demonstrate that commonly used gene transfer vectors induce a response reminiscent of stress activation in host cells, which needs to be taken into account when performing functional assays with transduced cells.

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The Mouse Cell Surface Protein TOSO Regulates Fas/Fas Ligand-induced Apoptosis through Its Binding to Fas-associated Death Domain

Abstract: Mouse TOSO, the homologue of human TOSO gene, was cloned and characterized in the present study. Using immunofluorescence confocal microscopy we localized TOSO to the cytoplasmic membrane of expressing cells.

Cited by 35 publications

References 32 publications

Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination

Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Indications for cell stress in response to adenoviral and baculoviral gene transfer observed by proteome profiling of human cancer cells

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