Defective endomembrane dynamics in Rab27a deficiency impairs nucleic acid sensing and cytokine secretion in immune cells
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-Quintial,
Ben A. Croker,
Jinzhong Zhang,
Hal Hoffman,
William B. Kiosses,
Catherine Hedrick,
Kersi Pestonjamasp,
Nathan Wineinger,
Roberto Baccala,
Sergio D. Catz
Affiliations
Juan Yu
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Elsa Meneses-Salas
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Jennifer L. Johnson
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Susanna Manenti
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Mouad Ait Kbaich
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Danni Chen
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Kasra Askari
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Jing He
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Aparna Shukla
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Binchu Shaji
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Rosana Gonzalez-Quintial
Department of Autoimmunity & Viral Immunopathology, San Diego BioMed Institute, San Diego, CA 92121, USA
Ben A. Croker
Department of Pediatrics, University of California San Diego; La Jolla, CA 92093, USA
Jinzhong Zhang
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Hal Hoffman
Department of Pediatrics, University of California San Diego; La Jolla, CA 92093, USA
William B. Kiosses
Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Catherine Hedrick
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Kersi Pestonjamasp
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Nathan Wineinger
Scripps Research Translational Institute, The Scripps Research Institute, La Jolla, CA 92037, USA
Roberto Baccala
Department of Autoimmunity & Viral Immunopathology, San Diego BioMed Institute, San Diego, CA 92121, USA
Sergio D. Catz
Department of Molecular and Cellular Biology, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
