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RNA functions in the selectivity of the Drosophila Innate Immune Response

Research unit

UPR 9022 - Réponse immunitaire et développement chez les insectes (IBMC)
15, rue Rene Descartes 67084 - Strasbourg Cedex

Group

Name: Génétique de la réponse immunitaire.

Group leader: REICHHART Jean-marc - jm.reichhart@unistra.fr

Group leader's phone: 0388417034

Website: Visit website

Group organization:
- Chercheurs: 3
- ITA: 2
- Doctorants: 2
- Post-Docs: 3
- Autres: 0

Publications of the team linked to the topic (3 last years):
1) 1) Bonnay F, Cohen-Berros E, Hoffmann M, Kimb SY, Boulianne GL, Hoffmann JA, Matt N, Reichhart JM. (2013) Big bang modulates gut immune tolerance in Drosophila. Proc. Natl. Acad. Sci. U S A 110, 2957-62.
2) 2) Deleury E, Dubreuil G, Elangovan N, Wajnberg E, Reichhart JM, Gourbal B, Duval D, Baron OL, Gouzy J, Coustau C (2012) Specific versus Non-Specific Immune Responses in an Invertebrate Species Evidenced by a Comparative de novo Sequencing Study. PLOS One 7, e32512.
3) 3) Kellenberger C, Leone P, Coquet L, Jouenne T, Reichhart JM, Roussel A. (2011) Structure-function analysis of grass clip serine protease involved in Drosophila Toll pathway activation. J Biol Chem. 286, 12300-12307.

About PhD

PhD Director: REICHHART Jean-marc - jm.reichhart@unistra.fr

Phone: 0388417034

Junior advisor: MATT Nicolas

Co-tutely: non

Co-Director: non

About PhD topic :

Title: RNA functions in the selectivity of the Drosophila Innate Immune Response

Project: The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear and aberrant regulation of NF-kB signaling is highly suspected in numerous cancers, inflammatory and autoimmune diseases. As a consequence, current anti-inflammatory agents act through inhibition of the NF-kB pathway to exert their therapeutic effects. Unfortunately, due to their lack of selectivity, these agents are also responsible for many side effects. These considerations emphasize the need for the development of more specific drugs, switching on or off only a subset of NF-kB target genes. Discovery of this new generation of drugs requires a prior comprehensive and large-scale dissection of the NF-kB pathways.
Our laboratory has been extensively investigating the innate immune response using forward genetic approaches in Drosophila. This led to the discovery of new small nuclear proteins, called Akirins, whose function is conserved form insects to mammals. Notably, we described that Akirins act at the level of the NF-κB factors to induce a full activation of NF-κB target genes during the innate immune response; their precise mode of action is however not known. There are two homologues of the Drosophila Akirin in mice and we demonstrated that Akirin-2 acts as a hub for NF-κB selectivity (Nature Immunology; Goto et al., 2008; Bonnay et al., Submitted). Based on this finding, we decided, using unbiased genome-wide proteomic and transcriptional approaches, to use Drosophila Akirin as a starting point to identify the mechanisms underlying NF-κB transcriptional selectivity and to re-explore the NF-κB pathway. A genome-wide proteomic analysis led us to the discovery of 9 proteins that are bona-fide partners of Akirin during the Drosophila innate immune response. We found that four of these proteins are RNA binding proteins and we propose accordingly to explore the role of RNAs (including Long none-coding RNA; LncRNA) in the control of the Drosophila innate immune response.

The proposed PhD project is based on two major aims.
First we propose to evaluate the role of these RNA-binding proteins in the innate immune response using RNA-interference and forward genetic approaches in various cellular models available in our laboratory and also in Drosophila.
Second we propose to sequence the RNAs bound to these Akirin-dependent RNA binding proteins (isolated by immune-precipitation) during the innate immune response in order to decipher their precise nature. We will particularly focus on the role of LncRNA during the innate immune response, which is still poorly documented.

Altogether, we expect that this research project will lead to a significant advance in the understanding of the mechanisms that govern both NF-kB selectivity during the innate immune response and the role of LncRNA during the NF-kB dependent transcription.

Wished skills: The appliquant must have a Master degree in biology/ molecular biology.

Expertises which will be acquired during the training: The PhD student will be immersed in an international working environment with competitive research topic. It will be mastering the tools of molecular biology as well as the techniques for insect and mammalian cells culture. Additionally, he will know how to manage colonies of transgenic flies.