Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria

Jonathan Bohlen, Qinhua Zhou, Quentin Philippot, Masato Ogishi, Darawan Rinchai, Tea Nieminen, Simin Seyedpour, Nima Parvaneh, Nima Rezaei, Niloufar Yazdanpanah, Mana Momenilandi, Clément Conil, Anna Lena Neehus, Carltin Schmidt, Carlos A. Arango-Franco, Tom Le Voyer, Taushif Khan, Rui Yang, Julia Puchan, Lucia ErazoMykola Roiuk, Taja Vatovec, Zarah Janda, Ivan Bagarić, Marie Materna, Adrian Gervais, Hailun Li, Jérémie Rosain, Jessica N. Peel, Yoann Seeleuthner, Ji Eun Han, Anne Sophie L'Honneur, Marcela Moncada-Vélez, Marta Martin-Fernandez, Michael E. Horesh, Tatiana Kochetkov, Monika Schmidt, Mohammed A. AlShehri, Eeva Salo, Harri Saxen, Gehad ElGhazali, Ahmad Yatim, Camille Soudée, Federica Sallusto, Armin Ensser, Nico Marr, Peng Zhang, Dusan Bogunovic, Aurélie Cobat, Mohammad Shahrooei, Vivien Béziat, Laurent Abel, Xiaochuan Wang, Stéphanie Boisson-Dupuis, Aurelio A. Teleman, Jacinta Bustamante, Qian Zhang, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

Abstract

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Original languageEnglish
Pages (from-to)5114-5134.e27
JournalCell
Volume186
Issue number23
DOIs
StatePublished - 9 Nov 2023

Keywords

  • IL-23
  • JAK2
  • MCTS1
  • MSMD
  • X-linked disease
  • inborn error of immunity
  • mycobacterium
  • translation re-initiation

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