Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia

David A. Martin; Lixin Zheng; Richard M. Siegel; Baohua Huang; Galen H. Fisher; Jin Wang; Christine E. Jackson; Jennifer M. Puck; Janet Dale; Stephen E. Straus; Marcus E. Peter; Peter H. Krammer; Stephen Fesik; Michael J. Lenardo

doi:10.1073/pnas.96.8.4552

Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia

David A. Martin, Lixin Zheng, Richard M. Siegel, Baohua Huang, Galen H. Fisher, Jin Wang, Christine E. Jackson, Jennifer M. Puck, Janet Dale, Stephen E. Straus, Marcus E. Peter, Peter H. Krammer, Stephen Fesik, Michael J. Lenardo

Research Institute

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Abstract

Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.

Original language	English (US)
Pages (from-to)	4552-4557
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	96
Issue number	8
DOIs	https://doi.org/10.1073/pnas.96.8.4552
State	Published - Apr 13 1999

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Martin, D. A., Zheng, L., Siegel, R. M., Huang, B., Fisher, G. H., Wang, J., Jackson, C. E., Puck, J. M., Dale, J., Straus, S. E., Peter, M. E., Krammer, P. H., Fesik, S., & Lenardo, M. J. (1999). Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia. Proceedings of the National Academy of Sciences of the United States of America, 96(8), 4552-4557. https://doi.org/10.1073/pnas.96.8.4552

Martin, DA, Zheng, L, Siegel, RM, Huang, B, Fisher, GH, Wang, J, Jackson, CE, Puck, JM, Dale, J, Straus, SE, Peter, ME, Krammer, PH, Fesik, S & Lenardo, MJ 1999, 'Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 8, pp. 4552-4557. https://doi.org/10.1073/pnas.96.8.4552

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title = "Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia",

abstract = "Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.",

author = "Martin, {David A.} and Lixin Zheng and Siegel, {Richard M.} and Baohua Huang and Fisher, {Galen H.} and Jin Wang and Jackson, {Christine E.} and Puck, {Jennifer M.} and Janet Dale and Straus, {Stephen E.} and Peter, {Marcus E.} and Krammer, {Peter H.} and Stephen Fesik and Lenardo, {Michael J.}",

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AU - Martin, David A.

AU - Zheng, Lixin

AU - Siegel, Richard M.

AU - Huang, Baohua

AU - Fisher, Galen H.

AU - Wang, Jin

AU - Jackson, Christine E.

AU - Puck, Jennifer M.

AU - Dale, Janet

AU - Straus, Stephen E.

AU - Peter, Marcus E.

AU - Krammer, Peter H.

AU - Fesik, Stephen

AU - Lenardo, Michael J.

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AB - Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.

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Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia

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