A conserved calcineurin-binding motif in human T lymphotropic virus type 1 p12I functions to modulate nuclear factor of activated T cell activation

Seung jae Kim, Wei Ding, Björn Albrecht, Patrick L. Green, Michael D. Lairmore

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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 p12I 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 p12I, 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 p12I and mutants of p12I that contained the motif-bound calcineurin. In addition, an alanine substitution p12I mutant (p12I AXAXAA) had greatly reduced binding affinity for calcineurin. We then tested whether p12I binding to calcineurin affected NFAT activity. p12I competed with NFAT for calcineurin binding in calmodulin bead pull-down experiments. Furthermore, the p12I AXAXAA mutant enhanced NFAT nuclear translocation compared with wild type p12I and increased NFAT transcriptional activity 2-fold greater than wild type p12I. Similar to NFAT, endogenous calcineurin phosphatase activity was increased in Jurkat T cells expressing p12I independent of its calcineurin binding property. Thus, the reduced binding of p12I 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 p12I modulates NFAT activation to promote early virus infection of T lymphocytes, providing a novel mechanism for retrovirus-mediated cell activation.

Original languageEnglish (US)
Pages (from-to)15550-15557
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
StatePublished - May 2 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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