The Cytoplasmic Domain of Fas Ligand Costimulates TCR Signals

Sun, Mingyi; Ames, Kristina; Suzuki, Ivy; Fink, Pamela J.

doi:10.4049/jimmunol.177.3.1481

Cited by 63 publications

(66 citation statements)

References 71 publications

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“…To define more precisely the role of ADAMs in FasL shedding, we used a panel of established MEF cell lines that were generated from mouse embryos with a targeted deletion of different ADAM proteases as 40 kDa FasL is cleaved in the extracellular domain by a protease activity, generating a soluble ectodomain (sFasL) and a membrane-bound 18 kDa NTF termed NTF1, which can be further processed. The antibody G247-4 reacts with an extracellular epitope, whereas Ab3 detects intracellular determinants.…”

Section: Resultsmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

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Section: Resultsmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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“…33 Much less is known about the molecular mechanisms underlying its capacity to transduce nonapoptotic signals into the ligand-bearing cell. FasL reverse signaling has been shown to enhance T-cell proliferation, [11][12][13] and a recent publication has demonstrated that expression of the cytoplasmic FasL domain alone is sufficient to costimulate T-cell receptor signals. 11 Nevertheless, it remains unclear exactly how the FasL ICD is engaged in the transmission of such costimulatory signals.…”

Section: Discussionmentioning

confidence: 99%

“…FasL reverse signaling has been shown to enhance T-cell proliferation, [11][12][13] and a recent publication has demonstrated that expression of the cytoplasmic FasL domain alone is sufficient to costimulate T-cell receptor signals. 11 Nevertheless, it remains unclear exactly how the FasL ICD is engaged in the transmission of such costimulatory signals. Our data reveal a novel regulated processing of endogenous FasL in T-cells by the metalloproteinase ADAM 10 and the intramembrane protease SPPL2a, which ultimately leads to liberation of the FasL ICD into the cytosol.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13] For example, crosslinking cell surface FasL during T-cell receptor activation led to maximal CD8 þ T-cell proliferation, indicating an ancillary role of FasL signaling in T-cell activation. [11][12][13] This phenomenon, known as 'reverse' or 'retrograde' signaling, has also been associated with other members of the TNF superfamily. Its common outcomes are changes in proliferation and cytokine production profiles of the affected cells.…”

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confidence: 99%

“…1 Interestingly, FasL reverse signaling leading to T-cell co-stimulation is induced by the expression of the FasL cytoplasmic domain alone. 11 The primary structure of the FasL protein suggests the presence of several signaling motifs within its intracellular portion that are well conserved across mammalian species ( 14 and references therein), for example, a casein kinase I (CKI) consensus site and a unique polyproline stretch. Different Src homology 3 (SH3)-or WW-domain-containing proteins have been reported to bind to the FasL proline-rich domain in various assays, 1 among them members of the Fes/CIP4 homology/SH3 protein family, which regulate subcellular FasL distribution.…”

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confidence: 99%

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The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Cahuzac²,

et al. 2007

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Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell deathinducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidaselike family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

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Reverse Signalling

Ross

Ali

Woo

et al. 2016

Encyclopedia of Life Sciences

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Cellular signal transduction is defined as the conversion of an extracellular signal to a response within a cell. Commonly referred to as forward signalling, this extracellular signal often comes in the form of a soluble ligand that binds to a membrane‐spanning receptor. However, many ligands or their precursors are also transmembrane or membrane associated. It is now appreciated that these ligands may also act as receptors in a process referred to as reverse signalling. There is a growing body of evidence that reverse signalling occurs for several classes of ligands including: ephrins, semaphorins, interleukins, tumour necrosis factor family members and Notch‐associated ligands. This type of signalling has been linked to immune responses, axon guidance, cell proliferation and differentiation. Here we review reverse signalling of ligands categorised by how they associate with the membrane: transmembrane type 1 (TM1), transmembrane type 2 (TM2), or GPI‐linked. Within this structure we will emphasize the physiological and pathological roles of reverse signaling. Key Concepts Ligand classes that possess the ability to reverse signal include, but are not limited to, members of the tumour necrosis factor superfamily (TNFSF), ephrin family, semaphorin family, interleukin family and Notch‐associated ligands. These ligands can be categorized into the following subgroups: transmembrane type 1 (TM1), transmembrane type 2 (TM2), and GPI‐linked. Ligands can reverse signal by directly recruiting adaptor or effector proteins, acting in concert with coreceptors or by liberation of the intracellular domain to influence transcription. Reverse signalling has been shown to be involved in processes including axon guidance, tissue development and immune responses. Ectopic regulation of reverse signalling is associated with a range of pathologies including cancer, developmental defects and osteoporosis.

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The Cytoplasmic Domain of Fas Ligand Costimulates TCR Signals

Cited by 63 publications

References 71 publications

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Reverse Signalling

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