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

  • Cell. 2023 Oct 18:S0092-8674(23)01078-4. doi: 10.1016/j.cell.2023.09.024.
Jonathan Bohlen  1 ,  Qinhua Zhou  2 ,  Quentin Philippot  3 ,  Masato Ogishi  4 ,  Darawan Rinchai  4 ,  Tea Nieminen  5 ,  Simin Seyedpour  6 ,  Nima Parvaneh  7 ,  Nima Rezaei  8 ,  Niloufar Yazdanpanah  8 ,  Mana Momenilandi  3 ,  Clément Conil  3 ,  Anna-Lena Neehus  3 ,  Carltin Schmidt  9 ,  Carlos A Arango-Franco  10 ,  Tom Le Voyer  3 ,  Taushif Khan  11 ,  Rui Yang  4 ,  Julia Puchan  12 ,  Lucia Erazo  3 ,  Mykola Roiuk  13 ,  Taja Vatovec  14 ,  Zarah Janda  14 ,  Ivan Bagarić  14 ,  Marie Materna  3 ,  Adrian Gervais  3 ,  Hailun Li  3 ,  Jérémie Rosain  3 ,  Jessica N Peel  4 ,  Yoann Seeleuthner  3 ,  Ji Eun Han  4 ,  Anne-Sophie L'Honneur  15 ,  Marcela Moncada-Vélez  4 ,  Marta Martin-Fernandez  16 ,  Michael E Horesh  16 ,  Tatiana Kochetkov  4 ,  Monika Schmidt  17 ,  Mohammed A AlShehri  18 ,  Eeva Salo  5 ,  Harri Saxen  5 ,  Gehad ElGhazali  19 ,  Ahmad Yatim  4 ,  Camille Soudée  3 ,  Federica Sallusto  20 ,  Armin Ensser  17 ,  Nico Marr  21 ,  Peng Zhang  4 ,  Dusan Bogunovic  16 ,  Aurélie Cobat  3 ,  Mohammad Shahrooei  22 ,  Vivien Béziat  23 ,  Laurent Abel  23 ,  Xiaochuan Wang  24 ,  Stéphanie Boisson-Dupuis  23 ,  Aurelio A Teleman  13 ,  Jacinta Bustamante  25 ,  Qian Zhang  23 ,  Jean-Laurent Casanova  26
Affiliations
  • 1. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg University, 69120 Heidelberg, Germany. Electronic address: [email protected].
  • 2. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Children's Hospital of Fudan University, 201102 Shanghai, China.
  • 3. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France.
  • 4. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
  • 5. New Children's Hospital, 00290 Helsinki, Finland.
  • 6. Research Center for Immunodeficiencies, Tehran University of Medical Sciences, P94V+8MF Tehran, Iran; Nanomedicine Research Association (NRA), P94V+8MF Tehran, Iran.
  • 7. Research Center for Immunodeficiencies, Tehran University of Medical Sciences, P94V+8MF Tehran, Iran; Department of Pediatrics, Tehran University of Medical Sciences, P94V+8MF Tehran, Iran; Children's Medical Center, P94V+8MF Tehran, Iran.
  • 8. Research Center for Immunodeficiencies, Tehran University of Medical Sciences, P94V+8MF Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 1419733151 Tehran, Iran.
  • 9. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Faculty of Medicine, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 10. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia.
  • 11. College of Health and Life Sciences, Hamad Bin Khalifa University, 8C8M+6Q Doha, Qatar; Department of Immunology, Sidra Medicine, 8C8M+6Q Doha, Qatar; The Jackson Laboratory, Farmington, CT, USA.
  • 12. Institute of Microbiology, ETH Zürich, 8049 Zürich, Switzerland.
  • 13. German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg University, 69120 Heidelberg, Germany.
  • 14. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; Heidelberg University, 69120 Heidelberg, Germany.
  • 15. Department of Virology, Cochin Hospital, AP-HP, 75015 Paris, France.
  • 16. Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School, New York, NY 10029, USA; Department of Pediatrics, Icahn School, New York, NY 10029, USA; Department of Microbiology, Icahn School, New York, NY 10029, USA.
  • 17. University Hospital Erlangen, Institute of Clinical and Molecular Virology, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 18. King Fahad Medical City, Children's Specialized Hospital, 12231 Riyadh, Saudi Arabia.
  • 19. Sheikh Khalifa Medical City- Union71, Purehealth, Abu Dhabi, United Arab Emirates, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
  • 20. Institute of Microbiology, ETH Zürich, 8049 Zürich, Switzerland; Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
  • 21. College of Health and Life Sciences, Hamad Bin Khalifa University, 8C8M+6Q Doha, Qatar; Department of Immunology, Sidra Medicine, 8C8M+6Q Doha, Qatar.
  • 22. Clinical and Diagnostic Immunology, KU Leuven, 3000 Leuven, Belgium; Dr. Shahrooei Laboratory, 22 Bahman St., Ashrafi Esfahani Blvd, Tehran, Iran.
  • 23. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
  • 24. Children's Hospital of Fudan University, 201102 Shanghai, China.
  • 25. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, 75015 Paris, France. Electronic address: [email protected].
  • 26. Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker hospital for sick children, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10032, USA; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. Electronic address: [email protected].
PMID: 37875108 DOI: 10.1016/j.cell.2023.09.024
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.

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