TY - JOUR
T1 - Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease
AU - le Voyer, Tom
AU - Neehus, Anna-Lena
AU - Yang, Rui
AU - Ogishi, Masato
AU - Rosain, J. rémie
AU - Alroqi, Fayhan
AU - Alshalan, Maha
AU - Blumental, Sophie
AU - Ali, Fatima Al
AU - Khan, Taushif
AU - Ata, Manar
AU - Rozen, Laurence
AU - Demulder, Anne
AU - Bastard, Paul
AU - Gruber, Conor
AU - Roynard, Manon
AU - Seeleuthener, Yoann
AU - Rapaport, Franck
AU - Bigio, Benedetta
AU - Chrabieh, Maya
AU - Sng, Danielle
AU - Berteloot, Laureline
AU - Boddaert, Nathalie
AU - Rozenberg, Flore
AU - Al-Muhsen, Saleh
AU - Bertoli-Avella, Aida
AU - Abel, Laurent
AU - Bogunovic, Dusan
AU - Marr, Nico
AU - Mansouri, Davood
AU - Mutairi, Fuad Al
AU - Béziat, Vivien
AU - Weil, Dominique
AU - Mahdaviani, Seyed Alireza
AU - Ferster, Alina
AU - Zhang, Shen-Ying
AU - Boisson-Dupuis, Stéphanie
AU - Reversade, Bruno
AU - Casanova, Jean-Laurent
AU - Bustamante, Jacinta
N1 - Funding Information:
ACKNOWLEDGMENTS. We warmly thank to Jie Chen and David Langlais for helpful discussions, and Yelena Nemirovskaya, Christine Rivalain, Dominick Papandrea, and Lazaro Lorenzo for administrative support. We also thank Stephen Elledge (Brigham and Women’s Hospital, Harvard University Medical School) for kindly providing the VirScan phage library used in this study. This research was supported, in part, by a grant from the National Institute of Allergy and Infectious Diseases (Grant R37AI095983), the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (Grant UL1TR001866), the Yale Center for Mendelian Genomics funded by the National Human Genome Research Institute (Grant UM1HG006504), the Genome Sequencing Project (GSP) Coordinating Center (Grant U24HG008956), the High Performance Computing Center (Research Infrastructure Program S10OD018521), The Rockefeller University, the St. Giles Foundation, National Institute of Health and Medical Research (INSERM), University of Paris, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (Grant EQU201903007798), the SCOR Corporate Foundation for Science, the French National Research Agency under the “Investments for the future” (Program ANR-10-IAHU-01) and GENMSMD (Grant ANR-16-CE17.0005-01, to J.B.), Sidra Medicine (Program SDR400048), a Strategic Positioning Fund for Genetic Orphan Diseases (Grant SPF2012/005), and an inaugural Use Inspired Basic Research (UIBR) grant from the Agency for Science, Technology and Research in Singapore (to B.R.). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, the New York Hideyo Noguchi Memorial Society, and the Cooperative Center on Human Immunology at The Rockefeller University. T.L.V, J.R., and P.B. are supported by the MD-PhD program of the Imagine Institute with the support of the Bettan-court-Schueller Foundation. A.-L.N. is supported by the international PhD program of the Imagine Institute with the support of the Bettancourt-Schueller Foundation. J.R. was also supported by a “poste d’Accueil INSERM.”
Funding Information:
We warmly thank to Jie Chen and David Langlais for helpful discussions, and Yelena Nemirovskaya, Christine Rivalain, Dominick Papandrea, and Lazaro Lorenzo for administrative support. We also thank Stephen Elledge (Brigham and Women's Hospital, Harvard University Medical School) for kindly providing the VirScan phage library used in this study. This research was supported, in part, by a grant from the National Institute of Allergy and Infectious Diseases (Grant R37AI095983), the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (Grant UL1TR001866), the Yale Center for Mendelian Genomics funded by the National Human Genome Research Institute (Grant UM1HG006504), the Genome Sequencing Project (GSP) Coordinating Center (Grant U24HG008956), the High Performance Computing Center (Research Infrastructure Program S10OD018521), The Rockefeller University, the St. Giles Foundation, National Institute of Health and Medical Research (INSERM), University of Paris, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (Grant EQU201903007798), the SCOR Corporate Foundation for Science, the French National Research Agency under the ?Investments for the future? (Program ANR-10-IAHU-01) and GENMSMD (Grant ANR-16-CE17.0005-01, to J.B.), Sidra Medicine (Program SDR400048), a Strategic Positioning Fund for Genetic Orphan Diseases (Grant SPF2012/005), and an inaugural Use Inspired Basic Research (UIBR) grant from the Agency for Science, Technology and Research in Singapore (to B.R.). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, the New York Hideyo Noguchi Memorial Society, and the Cooperative Center on Human Immunology at The Rockefeller University. T.L.V, J.R., and P.B. are supported by the MD-PhD program of the Imagine Institute with the support of the Bettancourt-Schueller Foundation. A.-L.N. is supported by the international PhD program of the Imagine Institute with the support of the Bettancourt-Schueller Foundation. J.R. was also supported by a ?poste d'Accueil INSERM.?
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/4/13
Y1 - 2021/4/13
N2 - Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.
AB - Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.
KW - Inborn error of immunity
KW - Inflammation
KW - Monocytosis
KW - Mycobacteria
KW - ZNFX1
UR - https://www.scopus.com/pages/publications/85104226664
U2 - 10.1073/pnas.2102804118
DO - 10.1073/pnas.2102804118
M3 - Article
C2 - 33876776
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
M1 - e2102804118
ER -
SDG 3 Good Health and Well-being