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The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity

Author

Listed:
  • Woelsung Yi

    (Hospital for Special Surgery)

  • Sanjay Gupta

    (Hospital for Special Surgery)

  • Edd Ricker

    (Weill Cornell Graduate School of Medical Sciences)

  • Michela Manni

    (Hospital for Special Surgery)

  • Rolf Jessberger

    (Technische Universität Dresden)

  • Yurii Chinenov

    (Hospital for Special Surgery
    Hospital for Special Surgery)

  • Henrik Molina

    (The Rockefeller University)

  • Alessandra B. Pernis

    (Hospital for Special Surgery
    Weill Cornell Graduate School of Medical Sciences
    Cornell University)

Abstract

Post-transcriptional modifications can control protein abundance, but the extent to which these alterations contribute to the expression of T helper (TH) lineage-defining factors is unknown. Tight regulation of Bcl6 expression, an essential transcription factor for T follicular helper (TFH) cells, is critical as aberrant TFH cell expansion is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we show that lack of the SLE risk variant Def6 results in deregulation of Bcl6 protein synthesis in T cells as a result of enhanced activation of the mTORC1–4E-BP–eIF4E axis, secondary to aberrant assembly of a raptor–p62–TRAF6 complex. Proteomic analysis reveals that this pathway selectively controls the abundance of a subset of proteins. Rapamycin or raptor deletion ameliorates the aberrant TFH cell expansion in mice lacking Def6. Thus deregulation of mTORC1-dependent pathways controlling protein synthesis can result in T-cell dysfunction, indicating a mechanism by which mTORC1 can promote autoimmunity.

Suggested Citation

  • Woelsung Yi & Sanjay Gupta & Edd Ricker & Michela Manni & Rolf Jessberger & Yurii Chinenov & Henrik Molina & Alessandra B. Pernis, 2017. "The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00348-3
    DOI: 10.1038/s41467-017-00348-3
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