A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95.

Constance Assohou-Luty; Jeanette Gerspach; Daniela Siegmund; Nicole Müller; Bertrand Huard; Gisa Tiegs; Klaus Pfizenmaier; Harald Wajant

A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95.

Standard

A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95. / Assohou-Luty, Constance; Gerspach, Jeanette; Siegmund, Daniela; Müller, Nicole; Huard, Bertrand; Tiegs, Gisa; Pfizenmaier, Klaus; Wajant, Harald.

In: J MOL MED, Vol. 84, No. 9, 9, 2006, p. 785-797.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Assohou-Luty, C, Gerspach, J, Siegmund, D, Müller, N, Huard, B, Tiegs, G, Pfizenmaier, K & Wajant, H 2006, 'A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95.', J MOL MED, vol. 84, no. 9, 9, pp. 785-797. <http://www.ncbi.nlm.nih.gov/pubmed/16924474?dopt=Citation>

APA

Assohou-Luty, C., Gerspach, J., Siegmund, D., Müller, N., Huard, B., Tiegs, G., Pfizenmaier, K., & Wajant, H. (2006). A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95. J MOL MED, 84(9), 785-797. [9]. http://www.ncbi.nlm.nih.gov/pubmed/16924474?dopt=Citation

Vancouver

Assohou-Luty C, Gerspach J, Siegmund D, Müller N, Huard B, Tiegs G et al. A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95. J MOL MED. 2006;84(9):785-797. 9.

Bibtex

@article{93b6c08d0d8f4164b6d9acb273c38f38,

title = "A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95.",

abstract = "We analyzed a novel bifunctional fusion protein, CD40ed-CD95Led, consisting amino-terminally of the extracellular domain of CD40 and carboxy-terminally of the extracellular domain of CD95L. On cells lacking CD40L, this fusion protein is poorly active with respect to CD95 activation [median effective dose (ED50)>1 microg/ml], but it stimulates CD95 signaling with high efficiency upon binding to membrane-expressed CD40L (ED50<1 ng/ml). Thus, cell surface immobilization mediated by the CD40 part of the molecule unmasks the high-latent, CD95-stimulating capacity of the otherwise poorly active CD95L fusion protein. Moreover, interaction of the CD40 part of CD40ed-CD95Led with CD40L prevents the activation of cellular CD40. The CD40ed-CD95Led fusion protein therefore simultaneously blocks antiapoptotic CD40 activation and induces CD95-mediated apoptosis. Indeed, T47D cells displaying an antiapoptotic autocrine CD40-CD40L signaling loop were significantly more sensitive toward CD40ed-CD95Led than toward soluble CD95L artificially activated by crosslinking. Fusion proteins of RANK and CD95L (RANKed-CD95Led) and CD40 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (CD40ed-TRAILed), with domain architectures similar to CD40ed-Cd95Led, displayed RANKL-dependent CD95 and CD40L-dependent TRAILR2 activation, respectively, indicating the principle feasibility of this fusion protein design.",

keywords = "Animals, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Structure, Tertiary, Protein Binding, *Signal Transduction, Cell Survival, Antigens, CD40/*immunology/metabolism, Antigens, CD95/*immunology/metabolism, CD40 Ligand/*immunology/metabolism, Cell Death, Cell Membrane/*metabolism, Fas Ligand Protein/*immunology/metabolism, RANK Ligand/metabolism, Receptor Activator of Nuclear Factor-kappa B/metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism, Recombinant Fusion Proteins/metabolism, TNF-Related Apoptosis-Inducing Ligand/metabolism, Animals, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Structure, Tertiary, Protein Binding, *Signal Transduction, Cell Survival, Antigens, CD40/*immunology/metabolism, Antigens, CD95/*immunology/metabolism, CD40 Ligand/*immunology/metabolism, Cell Death, Cell Membrane/*metabolism, Fas Ligand Protein/*immunology/metabolism, RANK Ligand/metabolism, Receptor Activator of Nuclear Factor-kappa B/metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism, Recombinant Fusion Proteins/metabolism, TNF-Related Apoptosis-Inducing Ligand/metabolism",

author = "Constance Assohou-Luty and Jeanette Gerspach and Daniela Siegmund and Nicole M{\"u}ller and Bertrand Huard and Gisa Tiegs and Klaus Pfizenmaier and Harald Wajant",

year = "2006",

language = "English",

volume = "84",

pages = "785--797",

journal = "J MOL MED",

issn = "0946-2716",

publisher = "Springer",

number = "9",

}

RIS

TY - JOUR

T1 - A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95.

AU - Assohou-Luty, Constance

AU - Gerspach, Jeanette

AU - Siegmund, Daniela

AU - Müller, Nicole

AU - Huard, Bertrand

AU - Tiegs, Gisa

AU - Pfizenmaier, Klaus

AU - Wajant, Harald

PY - 2006

Y1 - 2006

N2 - We analyzed a novel bifunctional fusion protein, CD40ed-CD95Led, consisting amino-terminally of the extracellular domain of CD40 and carboxy-terminally of the extracellular domain of CD95L. On cells lacking CD40L, this fusion protein is poorly active with respect to CD95 activation [median effective dose (ED50)>1 microg/ml], but it stimulates CD95 signaling with high efficiency upon binding to membrane-expressed CD40L (ED50<1 ng/ml). Thus, cell surface immobilization mediated by the CD40 part of the molecule unmasks the high-latent, CD95-stimulating capacity of the otherwise poorly active CD95L fusion protein. Moreover, interaction of the CD40 part of CD40ed-CD95Led with CD40L prevents the activation of cellular CD40. The CD40ed-CD95Led fusion protein therefore simultaneously blocks antiapoptotic CD40 activation and induces CD95-mediated apoptosis. Indeed, T47D cells displaying an antiapoptotic autocrine CD40-CD40L signaling loop were significantly more sensitive toward CD40ed-CD95Led than toward soluble CD95L artificially activated by crosslinking. Fusion proteins of RANK and CD95L (RANKed-CD95Led) and CD40 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (CD40ed-TRAILed), with domain architectures similar to CD40ed-Cd95Led, displayed RANKL-dependent CD95 and CD40L-dependent TRAILR2 activation, respectively, indicating the principle feasibility of this fusion protein design.

AB - We analyzed a novel bifunctional fusion protein, CD40ed-CD95Led, consisting amino-terminally of the extracellular domain of CD40 and carboxy-terminally of the extracellular domain of CD95L. On cells lacking CD40L, this fusion protein is poorly active with respect to CD95 activation [median effective dose (ED50)>1 microg/ml], but it stimulates CD95 signaling with high efficiency upon binding to membrane-expressed CD40L (ED50<1 ng/ml). Thus, cell surface immobilization mediated by the CD40 part of the molecule unmasks the high-latent, CD95-stimulating capacity of the otherwise poorly active CD95L fusion protein. Moreover, interaction of the CD40 part of CD40ed-CD95Led with CD40L prevents the activation of cellular CD40. The CD40ed-CD95Led fusion protein therefore simultaneously blocks antiapoptotic CD40 activation and induces CD95-mediated apoptosis. Indeed, T47D cells displaying an antiapoptotic autocrine CD40-CD40L signaling loop were significantly more sensitive toward CD40ed-CD95Led than toward soluble CD95L artificially activated by crosslinking. Fusion proteins of RANK and CD95L (RANKed-CD95Led) and CD40 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (CD40ed-TRAILed), with domain architectures similar to CD40ed-Cd95Led, displayed RANKL-dependent CD95 and CD40L-dependent TRAILR2 activation, respectively, indicating the principle feasibility of this fusion protein design.

KW - Animals

KW - Humans

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Protein Structure, Tertiary

KW - Protein Binding

KW - Signal Transduction

KW - Cell Survival

KW - Antigens, CD40/immunology/metabolism

KW - Antigens, CD95/immunology/metabolism

KW - CD40 Ligand/immunology/metabolism

KW - Cell Death

KW - Cell Membrane/metabolism

KW - Fas Ligand Protein/immunology/metabolism

KW - RANK Ligand/metabolism

KW - Receptor Activator of Nuclear Factor-kappa B/metabolism

KW - Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism

KW - Recombinant Fusion Proteins/metabolism

KW - TNF-Related Apoptosis-Inducing Ligand/metabolism

KW - Animals

KW - Humans

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Protein Structure, Tertiary

KW - Protein Binding

KW - Signal Transduction

KW - Cell Survival

KW - Antigens, CD40/immunology/metabolism

KW - Antigens, CD95/immunology/metabolism

KW - CD40 Ligand/immunology/metabolism

KW - Cell Death

KW - Cell Membrane/metabolism

KW - Fas Ligand Protein/immunology/metabolism

KW - RANK Ligand/metabolism

KW - Receptor Activator of Nuclear Factor-kappa B/metabolism

KW - Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism

KW - Recombinant Fusion Proteins/metabolism

KW - TNF-Related Apoptosis-Inducing Ligand/metabolism

M3 - SCORING: Journal article

VL - 84

SP - 785

EP - 797

JO - J MOL MED

JF - J MOL MED

SN - 0946-2716

IS - 9

M1 - 9

ER -