PLoS Pathogens, 2016, Vol.12(2)
Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes. Author Summary Trypanosoma brucei is a member of a large group of flagellated protozoan parasites that threatens the lives and husbandry of millions of people worldwide. This group includes parasites that cause devastating diseases such as leishmaniasis (caused by different species of Leishmania ) and Chagas disease in South America (caused by Trypanosoma cruzi ). One common feature of these parasites is a sophisticated life cycle, which requires transmission between a mammalian host and an insect vector. Over the course of this life cycle, the parasites follow a sequence of distinct developmental forms, which are perfectly adapted to the different host environments. We employed quantitative mass spectrometry techniques to unravel the molecular mechanisms that drive developmental differentiation of Trypanosoma brucei , the causative agent of African sleeping sickness. We followed the changes of expression of 4270 proteins during the development of the human-infective to the insect form of trypanosomes. The insights gained should help us to better understand not only how these dangerous parasites are able to survive in different environments, but also how they evade the defense mechanisms of their hosts. Unraveling the requirements needed for adaptation to human hosts might also be useful for targeted drug development to fight the devastating neglected tropical diseases caused by these parasites.
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