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Host microtubule plus-end binding protein CLASP1 influences sequential steps in the Trypanosoma cruzi infection process.
MedLine Citation:
PMID:  23107073     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Mammalian cell invasion by the protozoan parasite Trypanosoma cruzi involves host cell microtubule dynamics. Microtubules support kinesin-dependent anterograde trafficking of host lysosomes to the cell periphery where targeted lysosome exocytosis elicits remodeling of the plasma membrane and parasite invasion. Here, a novel role for microtubule plus-end tracking proteins (+TIPs) in the coordination of T. cruzi trypomastigote internalization and post-entry events is reported. Acute silencing of CLASP1, a +TIP that participates in microtubule stabilization at the cell periphery, impairs trypomastigote internalization without diminishing the capacity for calcium-regulated lysosome exocytosis. Subsequent fusion of the T. cruzi vacuole with host lysosomes and its juxtanuclear positioning are also delayed in CLASP1-depleted cells. These post-entry phenotypes correlate with a generalized impairment of minus-end directed transport of lysosomes in CLASP1 knockdown cells and mimic the effects of dynactin disruption. Consistent with GSK3β acting as a negative regulator of CLASP function, inhibition of GSK3β activity enhances T. cruzi entry in a CLASP1-dependent manner and expression of constitutively active GSK3β dampens infection. This study provides novel molecular insights into the T. cruzi infection process, emphasizing functional links between parasite-elicited signaling, host microtubule plus-end tracking proteins and dynein-based retrograde transport. Highlighted in this work is a previously unrecognized role for CLASPs in dynamic lysosome positioning, an important aspect of the nutrient sensing response in mammalian cells.
Authors:
Xiaoyan Zhao; Praveen Kumar; Sheena Shah-Simpson; Kacey L Caradonna; Niels Galjart; Crystal Teygong; Ira Blader; Torsten Wittmann; Barbara A Burleigh
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-26
Journal Detail:
Title:  Cellular microbiology     Volume:  -     ISSN:  1462-5822     ISO Abbreviation:  Cell. Microbiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100883691     Medline TA:  Cell Microbiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 Blackwell Publishing Ltd.
Affiliation:
Department of Immunology and Infectious Disease, Harvard School of Public Health, 665 Huntington Ave, Boston, MA, 02115.
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