Syntaxin 11 Binds Vti1b and Regulates Late Endosome to Lysosome Fusion in Macrophages

Authors

  • Carolin Offenhäuser,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
    2. Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia
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  • Nazi Lei,

    1. Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia
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  • Sandrine Roy,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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  • Brett M. Collins,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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  • Jennifer L. Stow,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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  • Rachael Z. Murray

    Corresponding author
    1. Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia
    2. Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia
      Rachael Z. Murray, rachaelm@chw.edu.au
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Rachael Z. Murray, rachaelm@chw.edu.au

Abstract

Syntaxin 11 (Stx11) is a SNARE protein enriched in cells of the immune system. Loss or mutation of Stx11 results in familial hemophagocytic lymphohistiocytosis type-4 (FHL-4), an autosomal recessive disorder of immune dysregulation characterized by high levels of inflammatory cytokines along with defects in T-cell and natural killer cell function. We show here Stx11 is located on endosomal membranes including late endosomes and lysosomes in macrophages. While Stx11 did not form a typical trans-SNARE complex, it did bind to the Q-SNARE Vti1b and was able to regulate the availability of Vti1b to form the Q-SNARE complexes Stx6/Stx7/Vtib and Stx7/Stx8/Vti1b. The mutant form of Stx11 sequestered Vti1b from forming the Q-SNARE complex that mediates late endosome to lysosome fusion. Depletion of Stx11 in activated macrophages leads to an accumulation of enlarged late endocytic compartments, increased trafficking to the cell surface and inhibition of late endosome to lysosome fusion. These phenotypes are rescued by the expression of an siRNA-resistant Stx11 construct in Stx11-depleted cells. Our results suggest that by regulating the availability of Vti1b, Stx11 regulates trafficking steps between late endosomes, lysosomes and the cell surface in macrophages.

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