Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)<sup>1</sup>

Ghadimi, Markus Philipp; Sanzenbacher, Ralf; Thiede, Bernd; Wenzel, Jennifer M.; Qian, Ji; Plomann, Markus; Borkhardt, Arndt; Kabelitz, Dieter; Janßen, Ottmar

doi:10.1016/s0014-5793(02)02709-6

Cited by 47 publications

(39 citation statements)

References 49 publications

(51 reference statements)

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“…Our data further indicate that the weakened cytotoxic potential of sFasL is in part due to loss of FasL Cyt , in addition to loss of multivalency as previously described (8). The observation that FasL PRD did not play a role in FasL-mediated cytotoxicity rules out the participation of potential FasL PRDinteracting proteins such as Grb2, Grap, p47 phox , and Nck in this process (12). Moreover, no interacting protein was detected using GST-FasL 2-29 (12).…”

Section: Fasl 2-33 But Not Fasl Prd Is Required For the Optimal Expresupporting

confidence: 80%

“…The observation that FasL PRD did not play a role in FasL-mediated cytotoxicity rules out the participation of potential FasL PRDinteracting proteins such as Grb2, Grap, p47 phox , and Nck in this process (12). Moreover, no interacting protein was detected using GST-FasL 2-29 (12). These data suggest the ability to optimize FasL cytotoxicity is intrinsic to FasL 2-33 .…”

Section: Fasl 2-33 But Not Fasl Prd Is Required For the Optimal Exprementioning

confidence: 90%

“…FasL Cyt contains PRD that may interact with certain cellular proteins (12). To determine whether FasL PRD plays a role in FasL-mediated cytotoxicity, we generated PRD-deleted (⌬PRD) FasL transfectants from Neuro-2a and COS-7 cell lines.…”

Section: Fasl 2-33 But Not Fasl Prd Is Required For the Optimal Exprementioning

confidence: 99%

“…The sequence of FasL Cyt is highly conserved among species, suggesting it may have specific functions (11)(12)(13)(14). Here, we report a novel function of FasL Cyt .…”

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confidence: 99%

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Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity

Jodo

Pidiyar

Xiao

et al. 2005

The Journal of Immunology

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The cytotoxic function of CD178 (Fas ligand (FasL)) is critical to the maintenance of peripheral tolerance and immune-mediated tissue pathology. The active site of FasL resides at the FasL extracellular region (FasLExt) and it functions through binding/cross-linking Fas receptor on target cells. In this study, we report that FasLExt-mediated cytotoxicity is regulated by the FasL cytoplasmic tail (FasLCyt). Deleting the N-terminal 2–70 aa (Δ70) or N-terminal 2–33 aa (Δ33) reduced the cytotoxic strength as much as 30- to 100-fold. By contrast, change in the cytotoxic strength was not observed with FasL deleted of the proline-rich domains (45–74 aa, ΔPRD) in the FasLCyt. Our study identifies a novel function of FasLCyt and demonstrates that FasL2–33, a sequence unique to FasL, is critically required for the optimal expression of FasLExt-mediated cytotoxicity.

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Section: Fasl 2-33 But Not Fasl Prd Is Required For the Optimal Expresupporting

confidence: 80%

Section: Fasl 2-33 But Not Fasl Prd Is Required For the Optimal Exprementioning

confidence: 90%

Section: Fasl 2-33 But Not Fasl Prd Is Required For the Optimal Exprementioning

confidence: 99%

“…The sequence of FasL Cyt is highly conserved among species, suggesting it may have specific functions (11)(12)(13)(14). Here, we report a novel function of FasL Cyt .…”

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confidence: 99%

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Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity

Jodo

Pidiyar

Xiao

et al. 2005

The Journal of Immunology

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“…From the various proteins that were identified as potential FasL interactors (8,9), the adaptor protein Nck attracted our attention in the context of T cell receptor (TCR)-induced vesicular transport and cytoskeletal reorganization. Nck is an adaptor protein that is built of a C-terminal Src homology (SH) 2 domain and three SH3 domains (Fig.…”

mentioning

confidence: 99%

The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse

Lettau

Qian

Linkermann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell. We propose that the FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the IS. Nck binds to the proline-rich portion of FasL and alters its subcellular distribution when coexpressed in 293T cells. In T lymphocytes, endogenous Nck partially colocalizes with lysosome-associated FasL. When T cell clones or lines are exposed to target cells, both proteins and other components of secretory lysosomes (i.e., granzyme B or cathepsin D) are transported to the cell-cell interface. The present data suggest that T cell receptor engagement provokes a rapid, tyrosine kinase-and actin-dependent transport of Nck-associated FasL-carrying lysosomes to the contact area. Our observations support the previous notion that the unique cytoplasmic tail of FasL is crucial for its directed transport to the cell surface and into the assembling cytotoxic IS.protein-protein interaction ͉ Src homology 3 domain ͉ secretory lysosomes ͉ T lymphocytes T he Fas ligand (FasL) (CD95L, APO1-L, and TNFSF6) is a type-II transmembrane protein belonging to the TNF family of death factors (1, 2). During primary stimulation of cytotoxic T lymphocytes and natural killer cells, newly synthesized FasL is directed to and stored in specialized secretory lysosomes (3, 4). Thus, in activated human T cells, FasL is a transmembrane component of these lytic granules that also contain granzymes and pore-forming perforin monomers (5). Upon interaction with a target cell, the lipid bilayer of the secretory lysosomes is believed to fuse with the plasma membrane, thereby releasing the soluble factors into the synapse and presenting FasL on the cell surface (4, 6). The molecular mechanisms that regulate the targeting of FasL to secretory lysosomes and the activation-dependent transport of these organelles to the immunological synapse (IS) are so far unknown.Because the intracellular localization of FasL depends on its proline-rich domain (PRD) (7), the identification and functional analysis of FasL PRD-interacting proteins should provide more information on regulators of the lysosomal association of FasL and its activation-dependent transport to the IS. From the various proteins that were identified as potential FasL interactors (8, 9), the adaptor protein Nck attracted our attention in the context of T cell receptor (TCR)-induced vesicular transport and cytoskeletal reorganization. Nck is an adaptor protein that is built of a C-terminal Src homology (SH) 2 domain and three SH3 domains (Fig. 1A). The main function of Nck is the regulation of an activation-dependent actin filament formation through its interacti...

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Programmed hepatocytes cell death associated with FLIP downregulation in response to extracellular PreS1/2

Rojas

Barboza

Terán-Ángel

et al. 2013

Journal of Medical Virology

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Chronic hepatitis B virus (HBV) infection involves liver damage resulting in continuous cell injury and death. During HBV infection, hepatocytes exhibit changes in death receptor expression and in their susceptibility to death. These changes are observed not only in infected cells but also in bystander cells. Because excess viral surface protein (HBsAg) is secreted in large amounts as soluble particles containing preS proteins, the role of soluble preS1/2 in hepatocyte (HepG2) death modulation is an important issue to be explored. An increase of cell death induced by preS1/2 was observed. Also, cell death was associated with the down-regulation of FLIP and activation of caspase 8, caspase 9, and BID. Additionally, hepatocytes exhibited a sensitization to death mediated by the Fas receptor. These results, may contribute to understanding the role of envelope proteins (preS1/2) in the pathogenesis of HBV infection.

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Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)¹

Cited by 47 publications

References 49 publications

Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity

Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity

The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse

Programmed hepatocytes cell death associated with FLIP downregulation in response to extracellular PreS1/2

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Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)1

Cited by 47 publications

References 49 publications

Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity

Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity

The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse

Programmed hepatocytes cell death associated with FLIP downregulation in response to extracellular PreS1/2

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Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)¹