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J. Biol. Chem., Vol. 278, Issue 18, 15550-15557, May 2, 2003

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A Conserved Calcineurin-binding Motif in Human T Lymphotropic Virus Type 1 p12^I Functions to Modulate Nuclear Factor of Activated T Cell Activation^*

Seung-jae Kim, Wei Ding, Björn Albrecht^§, Patrick L. Green^¶, and Michael D. Lairmore^¶**

From the  Center for Retrovirus Research and Department of Veterinary Biosciences, ^¶ Comprehensive Cancer Center, The Arthur G. James Cancer Hospital and Solove Research Institute, and the  Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, Ohio 43210-1093

The PXIXIT calcineurin binding motif or highly related sequences are found in a variety of calcineurin-binding proteins in yeast, mammalian cells, and viruses. The accessory protein p12^I encoded in the HTLV-1 pX ORF I promotes T cell activation during the early stages of HTLV-1 infection by activating nuclear factor of activated T cells (NFAT) through calcium release from the endoplasmic reticulum. We identified in p12^I, a conserved motif, which is highly homologous with the PXIXIT calcineurin-binding motif of NFAT. Both immunoprecipitation and calmodulin agarose bead pull-down assays indicated that wild type p12^I and mutants of p12^I that contained the motif-bound calcineurin. In addition, an alanine substitution p12^I mutant (p12^I AXAXAA) had greatly reduced binding affinity for calcineurin. We then tested whether p12^I binding to calcineurin affected NFAT activity. p12^I competed with NFAT for calcineurin binding in calmodulin bead pull-down experiments. Furthermore, the p12^I AXAXAA mutant enhanced NFAT nuclear translocation compared with wild type p12^I and increased NFAT transcriptional activity 2-fold greater than wild type p12^I. Similar to NFAT, endogenous calcineurin phosphatase activity was increased in Jurkat T cells expressing p12^I independent of its calcineurin binding property. Thus, the reduced binding of p12^I to calcineurin allows enhanced nuclear translocation and transcription mediated by NFAT. Herein, we are the first to identify a retroviral protein that binds calcineurin. Our data suggest that HTLV-1 p12^I modulates NFAT activation to promote early virus infection of T lymphocytes, providing a novel mechanism for retrovirus-mediated cell activation.

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