Defective endomembrane dynamics in Rab27a deficiency impairs nucleic acid sensing and cytokine secretion in immune cells

• DOI: 10.1016/j.celrep.2024.114598
• Publication Date: 2024-08-08T19:51:09Z
• Authors: Juan Yu; Elsa Meneses-Salas; Jennifer L. Johnson; Susanna Manenti; Mouad Ait Kbaich; Danni Chen; Kasra Askari; Jing He; Aparna Shukla; Binchu Shaji; Rosana Gonzalez-Q...; Ben A. Croker; Jinzhong Zhang; Hal Hoffman; William B. Kiosses; Catherine Hedrick; Kersi Pestonjamasp; Nathan Wineinger; Roberto Baccala; Sergio D. Catz
• Keywords: TLR7; TLR9

Endosomal Toll-like receptors (eTLRs) are essential for the sensing of non-self through RNA and DNA detection. Here, using spatiotemporal analysis vesicular dynamics, super-resolution microscopy studies, functional assays, we show that endomembrane defects associated with deficiency small GTPase Rab27a cause delayed eTLR ligand recognition, defective early signaling, impaired cytokine secretion. Rab27a-deficient neutrophils retention eTLRs in amphisomes internalization. Extracellular signal-regulated kinase (ERK) signaling β2-integrin upregulation, responses to TLR7 TLR9 ligands, deficiency. CpG-stimulated present increased tumor necrosis factor alpha (TNF-α) secretion decreased a selected group mediators, including interleukin (IL)-10. In vivo, CpG-challenged Rab27a-null mice production type I interferons (IFNs) IFN-γ, IFN-α defect is confirmed plasmacytoid dendritic cells. Our findings have significant implications immunodeficiency, inflammation, CpG adjuvant vaccination.