Host microtubule plus‐end binding protein CLASP1 influences sequential steps in the Trypanosoma cruzi infection process |
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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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Institution: | 1. Department of Immunology and Infectious Disease, Harvard School of Public Health, , Boston, MA, 02115 USA;2. Department of Cell and Tissue Biology, University of California San Francisco, , San Francisco, CA, 94143 USA;3. Department of Cell Biology and Genetics, Erasmus MC, , 3000 CA Rotterdam, the Netherlands;4. Departments of Microbiology and Immunology and Ophthalmology, , Oklahoma City, OK, 73104 USA |
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Abstract: | 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 remodelling of the plasma membrane and parasite invasion. Here, a novel role for microtubule plus‐end tracking proteins (+TIPs) in the co‐ordination 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 knock‐down cells and mimic the effects ofdynactin 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 signalling, 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. |
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