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Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):632-7. doi: 10.1073/pnas.1518079113. Epub 2015 Dec 31.

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;
2
Department of Biological Chemistry, University of California, Los Angeles, CA 90095;
3
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095;
4
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;
5
Department of Biological Chemistry, University of California, Los Angeles, CA 90095; Molecular Biology Institute, University of California, Los Angeles, CA 90095 jwohl@mednet.ucla.edu kenthill@microbio.ucla.edu.
6
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Molecular Biology Institute, University of California, Los Angeles, CA 90095 jwohl@mednet.ucla.edu kenthill@microbio.ucla.edu.

Abstract

Cilia (eukaryotic flagella) are present in diverse eukaryotic lineages and have essential motility and sensory functions. The cilium's capacity to sense and transduce extracellular signals depends on dynamic trafficking of ciliary membrane proteins. This trafficking is often mediated by the Bardet-Biedl Syndrome complex (BBSome), a protein complex for which the precise subcellular distribution and mechanisms of action are unclear. In humans, BBSome defects perturb ciliary membrane protein distribution and manifest clinically as Bardet-Biedl Syndrome. Cilia are also important in several parasites that cause tremendous human suffering worldwide, yet biology of the parasite BBSome remains largely unexplored. We examined BBSome functions in Trypanosoma brucei, a flagellated protozoan parasite that causes African sleeping sickness in humans. We report that T. brucei BBS proteins assemble into a BBSome that interacts with clathrin and is localized to membranes of the flagellar pocket and adjacent cytoplasmic vesicles. Using BBS gene knockouts and a mouse infection model, we show the T. brucei BBSome is dispensable for flagellar assembly, motility, bulk endocytosis, and cell viability but required for parasite virulence. Quantitative proteomics reveal alterations in the parasite surface proteome of BBSome mutants, suggesting that virulence defects are caused by failure to maintain fidelity of the host-parasite interface. Interestingly, among proteins altered are those with ubiquitination-dependent localization, and we find that the BBSome interacts with ubiquitin. Collectively, our data indicate that the BBSome facilitates endocytic sorting of select membrane proteins at the base of the cilium, illuminating BBSome roles at a critical host-pathogen interface and offering insights into BBSome molecular mechanisms.

KEYWORDS:

BBSome; cilium; clathrin; ubiquitin; virulence

PMID:
26721397
PMCID:
PMC4725476
DOI:
10.1073/pnas.1518079113
[Indexed for MEDLINE]
Free PMC Article

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