IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes
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 <i>ALPK1</i> 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 <i>TIFA</i> upregulation in monocytes, and <i>TIFA</i> induction was sufficient to recapitulate the licensing effect of IFN-γ. IFN-γ treatment promoted the phenotypic expression of pathogenic <i>ALPK1</i> 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.
Authors
- Georgina Maalouf (ORCID: https://orcid.org/0000-0002-4554-1922)
- Pauline Bronnec (ORCID: https://orcid.org/0009-0002-1942-7621)
- P. Sève (ORCID: https://orcid.org/0000-0003-3070-3842)
- Yvan Jamilloux (ORCID: https://orcid.org/0000-0001-5249-3650)
- M. Marcotte (ORCID: https://orcid.org/0009-0005-7258-9090)
- Nora Martel (ORCID: https://orcid.org/0009-0000-3597-1008)
- Thomas Henry (ORCID: https://orcid.org/0000-0002-0687-8565)
- David Saadoun (ORCID: https://orcid.org/0000-0003-3628-9996)
- Amandine Martin
- Etienne Garneret
- S. Caron
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR)
- Hospices Civils de Lyon (FR)
- Centre d'Immunologie et des Maladies Infectieuses (FR)
- Centre International de Recherche en Infectiologie (FR)
- Immunologie - Immunopathologie - Immunothérapie (FR)
Publication Details
- Journal
- iScience
- Published
- 2024-12-10
- DOI
- https://doi.org/10.1016/j.isci.2024.111563
- Citations
- 3
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.85
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Université Claude Bernard Lyon 1
- Assistance publique-Hôpitaux de Paris
- École Normale Supérieure de Lyon