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

• Published in: Cell reports (Cambridge) Vol. 43; no. 8; p. 114598
• Main Authors: Yu, Juan, Meneses-Salas, Elsa, Johnson, Jennifer L., Manenti, Susanna, Kbaich, Mouad Ait, Chen, Danni, Askari, Kasra, He, Jing, Shukla, Aparna, Shaji, Binchu, Gonzalez-Quintial, Rosana, Croker, Ben A., Zhang, Jinzhong, Hoffman, Hal, Kiosses, William B., Hedrick, Catherine, Pestonjamasp, Kersi, Wineinger, Nathan, Baccala, Roberto, Catz, Sergio D.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 27.08.2024; Elsevier
• Subjects: amphisome; CP: Cell biology; CP: Immunology; CpG; endosomal Toll-like receptor; IFN-α; IL-10; neutrophil; plasmacytoid Dendritic Cell; Rab GTPase; TLR7; TLR9; IFN-α; plasmacytoid Dendritic Cell; CP: Immunology; Rab GTPase; amphisome; CP: Cell biology; endosomal Toll-like receptor; TLR9; TLR7; CpG; neutrophil; IL-10
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114598

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. [Display omitted] •Rab27a deficiency causes retention of eTLRs in LC3B/LAMP1+ amphisomes•Delayed CpG internalization impaired early eTLR signaling in Rab27a-null neutrophils•Rab27a is required for IL-10 and IFN-α secretion independently of eTLR signaling•CpG-challenged Rab27a-null mice show decreased type I IFN secretion Yu et al. demonstrate that, in the absence of Rab27a, endosomal Toll-like receptors are retained at amphisomes and CpG internalization is delayed. CpG-stimulated Rab27a-deficient neutrophils present selective defects in cytokine secretion. Defective nucleic acid sensing and altered cytokine secretion in Rab27a deficiency contribute to infection susceptibility and inflammatory disease.