2. Academic Validation
  3. Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria

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

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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