ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination

Mohammed Ali Akbar, Rajakumar Mandraju, Charles Tracy, Wei Hu, Chandrashekhar Pasare, Helmut Krämer

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B.

Original languageEnglish (US)
Pages (from-to)267-279
Number of pages13
JournalImmunity
Volume45
Issue number2
DOIs
StatePublished - 2016

Keywords

  • ARC syndrome
  • LPS
  • Phagocytosis
  • TLR signaling
  • Tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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