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Modulation of juvenile hormone signaling by receptor phosphorylation

Periodic Reporting for period 1 - JHSIGNAL (Modulation of juvenile hormone signaling by receptor phosphorylation)

Reporting period: 2017-01-01 to 2018-12-31

H2020-MSCA-IF-2015-RI-708832 JHSIGNAL

Project Title: Modulation of juvenile hormone signaling by receptor phosphorylation

Juvenile hormones (JHs) govern many aspects of insect and related arthropod development and reproduction. Species relying on regulation by JH range from beneficial pollinators to agricultural pests and disease vectors. Thorough understanding of JH signaling is therefore essential for development of targeted JH-based insecticides, a direct benefit to the society. The intracellular JH receptor has been identified only recently and its actions are still poorly understood. Current evidence suggests that activity of JH receptor is modulated by JH-induced phosphorylation. The main research objective of this MSCA project was to identify the phosphorylation target sites of JH receptor and to determine their significance for its function. An equally important objective of this Fellowship was to facilitate a full reintegration of the Fellow, an erudite biochemist with 20 years of experience from top-ranking US institutions, back into Czech and European science environment.

Conclusions of the action:
We believe that the project has fully achieved its objectives and milestones for the period yielding new and important findings described below. The Marie Curie program is an excellent and unique opportunity for researches at various stages of their career, and we only hope that similar platforms will be available in future.
The main research results:

Over the two-year course of the project, the Fellow has established herself as a valuable asset of Dr. Jindra’s research team. She demonstrated her research skills in a study aimed at better mechanistic understanding of JH signaling. This investigation has been carried out in a collaboration with a leading Czech scientific institution, the Institute of Organic Chemistry and Biochemistry (IOCB) in Prague. The joined research effort resulted in a high-quality publication on ligand stereoselectivity of JH receptor with the first authorship for the Fellow (Bittova et al (2019) J.Biol. Chem. 294, 410-423). The Fellow has also participated in a study on JH receptor structure and function pursued in collaboration with the Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO). That contribution has earned the Fellow an authorship on a manuscript ready for submission (Jindra, M. , McKinstry, B., Nebl, T., Bittova, L., Ren, B., Xu, Z., Shaw, J., Phan, T., Lu, L., Low, J., Mackay J., Song, X., Sparrow, L., Lovrecz, G. and Hill, R.: Characterisation of Purified Recombinant Juvenile Hormone Receptor Proteins from Tribolium castaneum and Aedes aegypti).

The collaboration with CSIRO jump-started the current MSCA project by providing crucial data on phosphorylation target sites of JH receptor (JHR). Based on this information, three specific aims have been proposed to study: (1)Effects of JHR phosphorylation on JH-dependent transcription and JH binding (2) Effects of JHR phosphorylation on nuclear localization and protein-protein interactions (3) Role of JHR phosphorylation in JH-signaling in vivo.

The Fellow has made a major progress on all these aims. Importantly, novel nuclear localization signal motifs in both T. castaneum and D. melanogaster JHR were discovered in the course of this work. Very exciting findings came from mutations in phoshorylation sites of Drosophila JHR. Flies with mutated JHR display strong developmental defects, such as rotated genitalia in males or reduced fertility.

Together, these promising results have already started to reveal novel and significant aspects of JHR signaling mechanism. They will certainly improve our understanding of the role of post-translational modifications in regulation of insect development.

In the two-year course of the MSCA fellowship, the Fellow has mastered the basics of insect developmental genetics in both theory and practice, greatly expanding her research potential. She is now able to design and carry out independent experiments in her newly adopted field.

Dissemination and communication:

Besides an excellent progress on the proposed research listed above, the Fellow has made a strong connection with the local scientific and public community:
The Fellow took a major part in collaboration with IOCB, a leading Czech scientific institution, that yielded a Nature index journal publication mentioned above. The Fellow has exerted her teaching experience at the University of South Bohemia, teaching four semesters of biochemistry practicals for an elite Bachelor’s Programme „Biological Chemistry“. The Fellow gave a lecture about her work at Jírovcova highschool with an enthusiastic feedback from both students and teachers.

The Fellow has been actively engaged in promoting her research interests in public: She has been invited to the Czech broadcasting company as an „Afternoon guest“ to familiarize the public with new trends in bioscience. She covered a similar topic in a public „Academic half-hour“ lecture series organized by Biology Centre CAS. The Fellow took an opportunity to share her experience with writing a successful MSCA proposal and implementing the awarded fellowship in a seminar organized by the Regional Contact Organization South Bohemia in collaboration with Technology Centre CAS.
Potential impact and use of the results
The H2020-MSCA Individual Fellowship program has had a tremendous impact on the Fellow's career as it dramatically increased her chances of successful application for domestic and European grants and thus becoming established as a Czech scientist.
The Fellow has transferred to the host institution the much needed knowledge of protein biochemistry, cloning and tissue culture skills while the host provided an excellent training in molecular genetics and developmental biology of insects.
The Host institute has been taking great care to facilitate all the aspects of the Fellow‘s integration and career development, including assistance with funding, publications, administrative help, public outreach and possibilities to establish new collaborations, while keeping in mind the ultimate goal of the fellowship: genuine and permanent reintegration of the Fellow at the BC CAS in the Czech Republic. Thanks to MSCA fellowship, the Fellow has reached a new level of professional maturity in her research career. With the newly acquired skills, connections and publications, the Fellow is now in much better position to successfully apply for an autonomous funding.

A primary goal of this fundamental research investigation has been to produce high-profile scientific publications and thus stay at the lead of JH research in the world. The above-mentioned publications (Bittova et al (2019) J.Biol. Chem. 294, 410-423) and soon-to be-published results highlighted in this report fulfill our hopes and expectations.

Socio-economic impact:
Almost 3% of insect population disappear each year. The rate of decline of this essential group of invertebrates is alarming. Better understanding of the basic aspects of insect physiology, the main objective of this project, is key to maintaining balanced ecosystems around the world.
Workflow and current achievements, work in progress, and outlook of the project