Defective endomembrane dynamics in Rab27a deficiency impairs nucleic acid sensing and cytokine secretion in immune cells
Endosomal Toll-like receptors (eTLRs) are essential for the sensing of non-self through RNA and DNA detection. Here, using spatiotemporal analysis of vesicular dynamics, super-resolution microscopy studies, and functional assays, we show that endomembrane defects associated with the deficiency of the small GTPase Rab27a cause delayed eTLR ligand recognition, defective early signaling, and impaired cytokine secretion. Rab27a-deficient neutrophils show retention of eTLRs in amphisomes and impaired ligand internalization. Extracellular signal-regulated kinase (ERK) signaling and β2-integrin upregulation, early responses to TLR7 and TLR9 ligands, are defective in Rab27a deficiency. CpG-stimulated Rab27a-deficient neutrophils present increased tumor necrosis factor alpha (TNF-α) secretion and decreased secretion of a selected group of mediators, including interleukin (IL)-10. In vivo, CpG-challenged Rab27a-null mice show decreased production of type I interferons (IFNs) and IFN-γ, and the IFN-α secretion defect is confirmed in Rab27a-null plasmacytoid dendritic cells. Our findings have significant implications for immunodeficiency, inflammation, and CpG adjuvant vaccination.
Authors
- Elsa Meneses‐Salas (ORCID: https://orcid.org/0000-0001-7550-253X)
- Binchu V. Shaji (ORCID: https://orcid.org/0000-0001-6824-419X)
- Kasra Askari (ORCID: https://orcid.org/0000-0003-0938-8972)
- Sergio Daniel Catz (ORCID: https://orcid.org/0000-0002-1873-0277)
- Rosana González‐Quintial
- Hal M. Hoffman (ORCID: https://orcid.org/0000-0001-8609-2548)
- Aparna Shukla (ORCID: https://orcid.org/0000-0001-6048-5386)
- William Bill Kiosses (ORCID: https://orcid.org/0000-0003-1832-9050)
- Susanna Manenti (ORCID: https://orcid.org/0000-0001-8446-1418)
- Kersi Pestonjamasp (ORCID: https://orcid.org/0000-0001-8586-303X)
- Catherine C. Hedrick (ORCID: https://orcid.org/0000-0003-2045-4117)
- Jinzhong Zhang (ORCID: https://orcid.org/0000-0002-2540-2749)
- Nathan E. Wineinger (ORCID: https://orcid.org/0000-0003-4517-228X)
- Yu Zhou (ORCID: https://orcid.org/0009-0001-7093-1586)
- Ben A. Croker (ORCID: https://orcid.org/0000-0002-0885-3599)
- Roberto Baccalà (ORCID: https://orcid.org/0000-0002-3159-8469)
- Jing He (ORCID: https://orcid.org/0009-0002-0404-5276)
- Mouad Ait Kbaich
- Jennifer L. Johnson
- Danni Chen (ORCID: https://orcid.org/0000-0002-6003-8284)
Institutions
- Scripps Research Institute (US)
- La Jolla Institute for Immunology (US)
- Augusta University (US)
- University of California San Diego (US)
- La Jolla Alcohol Research (US)
- Biomed Research Institute (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114598
- Citations
- 2
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.48
Funders
- Cystinosis Research Foundation
- National Institutes of Health
- U.S. Public Health Service