IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes
Summary: Alpha-kinase 1 (ALPK1) is an immune receptor sensing the bacterial nucleotide sugar ADP-heptose. ALPK1 phosphorylates TIFA leading to its oligomerization and downstream NF-κB activation. Specific mutations in ALPK1 are associated with an autoinflammatory syndrome termed ROSAH and with spira...
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Elsevier
2025-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224027901 |
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| author | Amandine Martin Solène Caron Mélissa Marcotte Pauline Bronnec Etienne Garneret Nora Martel Georgina Maalouf Pascal Sève David Saadoun Yvan Jamilloux Thomas Henry |
| author_facet | Amandine Martin Solène Caron Mélissa Marcotte Pauline Bronnec Etienne Garneret Nora Martel Georgina Maalouf Pascal Sève David Saadoun Yvan Jamilloux Thomas Henry |
| author_sort | Amandine Martin |
| collection | DOAJ |
| description | Summary: Alpha-kinase 1 (ALPK1) is an immune receptor sensing the bacterial nucleotide sugar ADP-heptose. ALPK1 phosphorylates TIFA leading to its oligomerization and downstream NF-κB activation. Specific mutations in ALPK1 are associated with an autoinflammatory syndrome termed ROSAH and with spiradenoma (skin cancers with sweat gland differentiation). This study investigated ALPK1 responses in human mononuclear cells and demonstrates that human mononuclear cells have distinct abilities to respond to ADP-heptose. Notably, IFN-γ is required to license the ALPK1/TIFA pathway in monocytes, while it was dispensable for the responsiveness of B cells. IFN-γ induced TIFA upregulation in monocytes, and TIFA induction was sufficient to recapitulate the licensing effect of IFN-γ. IFN-γ treatment promoted the phenotypic expression of pathogenic ALPK1 mutations. The licensing effect of IFN-γ in monocytes was blocked by JAK inhibitors. These findings underscore the critical role of IFN-γ in ALPK1 function and suggest JAK inhibitors as potential therapies for ALPK1-related inflammatory conditions. |
| format | Article |
| id | doaj-art-104e752359b247709350b0a3150bb9cf |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-104e752359b247709350b0a3150bb9cf2025-01-05T04:28:31ZengElsevieriScience2589-00422025-01-01281111563IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytesAmandine Martin0Solène Caron1Mélissa Marcotte2Pauline Bronnec3Etienne Garneret4Nora Martel5Georgina Maalouf6Pascal Sève7David Saadoun8Yvan Jamilloux9Thomas Henry10CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, FranceCIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, FranceCIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, FranceCIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, FranceCIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, FranceCeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France; Internal Medicine, University Hospital Croix-Rousse, Hospices Civils de Lyon, 69000 Lyon, FranceCeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France; Department of Internal Medicine and Clinical Immunology, Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Références Maladies Auto-immunes et Systémiques Rares, INSERM, UMR S959, Immunology-Immunopathology-Immunotherapy (I3), 83 Boulevard de L’hôpital, 75013 Paris, FranceCeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France; Internal Medicine, University Hospital Croix-Rousse, Hospices Civils de Lyon, 69000 Lyon, FranceCeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France; Department of Internal Medicine and Clinical Immunology, Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Références Maladies Auto-immunes et Systémiques Rares, INSERM, UMR S959, Immunology-Immunopathology-Immunotherapy (I3), 83 Boulevard de L’hôpital, 75013 Paris, FranceCIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, France; CeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France; Internal Medicine, University Hospital Croix-Rousse, Hospices Civils de Lyon, 69000 Lyon, France; Corresponding authorCIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, France; CeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France; Corresponding authorSummary: Alpha-kinase 1 (ALPK1) is an immune receptor sensing the bacterial nucleotide sugar ADP-heptose. ALPK1 phosphorylates TIFA leading to its oligomerization and downstream NF-κB activation. Specific mutations in ALPK1 are associated with an autoinflammatory syndrome termed ROSAH and with spiradenoma (skin cancers with sweat gland differentiation). This study investigated ALPK1 responses in human mononuclear cells and demonstrates that human mononuclear cells have distinct abilities to respond to ADP-heptose. Notably, IFN-γ is required to license the ALPK1/TIFA pathway in monocytes, while it was dispensable for the responsiveness of B cells. IFN-γ induced TIFA upregulation in monocytes, and TIFA induction was sufficient to recapitulate the licensing effect of IFN-γ. IFN-γ treatment promoted the phenotypic expression of pathogenic ALPK1 mutations. The licensing effect of IFN-γ in monocytes was blocked by JAK inhibitors. These findings underscore the critical role of IFN-γ in ALPK1 function and suggest JAK inhibitors as potential therapies for ALPK1-related inflammatory conditions.http://www.sciencedirect.com/science/article/pii/S2589004224027901Natural sciencesBiological sciencesImmunology |
| spellingShingle | Amandine Martin Solène Caron Mélissa Marcotte Pauline Bronnec Etienne Garneret Nora Martel Georgina Maalouf Pascal Sève David Saadoun Yvan Jamilloux Thomas Henry IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes iScience Natural sciences Biological sciences Immunology |
| title | IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes |
| title_full | IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes |
| title_fullStr | IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes |
| title_full_unstemmed | IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes |
| title_short | IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes |
| title_sort | ifn γ licenses normal and pathogenic alpk1 tifa pathway in human monocytes |
| topic | Natural sciences Biological sciences Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224027901 |
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