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*

*Corresponding author for this work

Research output: Contribution to journalArticle

150 Scopus citations

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 languageEnglish (US)
Pages (from-to)4552-4557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number8
DOIs
StatePublished - Apr 13 1999

ASJC Scopus subject areas

  • General

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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