Bruton's Tyrosine Kinase (BTK) and Vav1 Contribute to Dectin1-Dependent Phagocytosis of Candida albicans in Macrophages

PLoS Pathogens

Sergio Grinstein¹  Gregory D. Fairn¹  Hidde L. Ploegh²  Karin Strijbis³  Alexandre Esteban³  Nicki Watson³  Valmik K. Vyas³  Eric Spooner³  Martin D. Witte³  Fikadu G. Tafesse³  Stephanie K. Dougan³  Gerald R. Fink³ 

[1] Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, Ontario, Canada;Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada;Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America

关键词: Phagocytosis;    C;    ida albicans;    Macrophages;    Phagosomes;    Kidneys;    Membrane proteins;    Yeast infections;    Phosphorylation;   

DOI  :  10.1371/journal.ppat.1003446

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Phagocytosis of the opportunistic fungal pathogen Candida albicans by cells of the innate immune system is vital to prevent infection. Dectin-1 is the major phagocytic receptor involved in anti-fungal immunity. We identify two new interacting proteins of Dectin-1 in macrophages, Bruton's Tyrosine Kinase (BTK) and Vav1. BTK and Vav1 are recruited to phagocytic cups containing C. albicans yeasts or hyphae but are absent from mature phagosomes. BTK and Vav1 localize to cuff regions surrounding the hyphae, while Dectin-1 lines the full length of the phagosome. BTK and Vav1 colocalize with the lipid PI(3,4,5)P3 and F-actin at the phagocytic cup, but not with diacylglycerol (DAG) which marks more mature phagosomal membranes. Using a selective BTK inhibitor, we show that BTK contributes to DAG synthesis at the phagocytic cup and the subsequent recruitment of PKCε. BTK- or Vav1-deficient peritoneal macrophages display a defect in both zymosan and C. albicans phagocytosis. Bone marrow-derived macrophages that lack BTK or Vav1 show reduced uptake of C. albicans, comparable to Dectin1-deficient cells. BTK- or Vav1-deficient mice are more susceptible to systemic C. albicans infection than wild type mice. This work identifies an important role for BTK and Vav1 in immune responses against C. albicans.

【 授权许可】

CC BY