STK25 and TAO Regulate Muscle-Specific Transcription and Muscle Function in the Parasitic Flatworm Schistosoma Mansoni

Date

August 2021

Authors

Paz, Carlos Alberto

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Abstract

Schistosomiasis, a disease caused by parasitic flatworms called schistosomes, affects 240 million people in developing regions, including large parts of Africa, Asia, and South America. In some of these areas, the disease affects over 50% of the population, making Schistosomiasis second only to Malaria in parasite devastation. To look for functionally important schistosome genes, we performed a large-scale RNAi screen in adult Schistosoma mansoni, and discovered 3 genes that produce an identical type of sickness in the worm. Disruption of the genes thousand-and-one kinase (TAO), serine threonine kinase 25 (STK25), or cerebral cavernous malformations 3 (CCM3) by RNAi in these worms produces a rapid and consistent deterioration consisting of detachment from the culture dish, drastic length reduction, selective paralysis in the worm body, and a distinctive "banana"-shaped morphology. Transplantation of stk25(RNAi) or tao(RNAi)- treated worms into a mouse host results in a significant reduction of worm eggs, and associated liver pathology, compared to healthy worm transplantations. RNA sequencing of stk25(RNAi) and tao(RNAi) worms uncovered that not only do both stk25 and tao cause significant transcriptional changes, but those changes are unusually similar, supporting the model that these genes are interacting as part of a signaling pathway in the worm. RNAi-induced transcriptional changes were heavily biased to worm muscle, a clue to explain loss of movement in these worms. By visualizing gene expression as well as muscle structure in whole worms, we concluded that these worms undergo specific loss of gene expression in the muscle cells of the body, but without significant loss of muscle cells or structure. Additionally, we find that schistosome TAO kinase can directly phosphorylate schistosome STK25 in vitro, and that this phosphorylation occurs at an amino acid (T173) which is known to be required for activation of all homologous STK25 kinases in other organisms. Using a yeast 2-hybrid system, we find that schistosome STK25 and CCM3 can physically interact, in agreement with literature reporting this interaction in other organisms. Altogether, our data supports a model that these genes work together in the parasite to control a muscle-specific transcriptional program that is essential for worm health both in culture and in the host.

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