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

Woelsung Yi, Sanjay Gupta, Edd Ricker, Michela Manni, Rolf Jessberger, Yurii Chinenov, Henrik Molina and Alessandra B. Pernis ()
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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
Henrik Molina: The Rockefeller University
Alessandra B. Pernis: Hospital for Special Surgery

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00348-3

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