RM5: 2006, March 16-18, RUBICON kick-off meeting: summary, Aske kursgård, Sweden (»Add to Infobox)

Haguenauer-Tsapis Rosine

Rosine Haguenauer-Tsapis's Group

The kick-off meeting of the RUBICON Network took place on 16-18 March, 2006 at “Aske kursgård”, a country-side manor situated 30 km from Arlanda airport, 50 km north-west of Stockholm City.

The Rubicon kick-off meeting was held in Aske Kursgard, Bro, near Stockholm. We were hosted in a nice XIX the century Swedish country manor that has been restyled to accommodate a medium size conference facility. The beautiful snow-covered sunny landscape was visible from the large windows of the modern conference room. Walking in the surroundings was pleasant, and the individual rooms nicely decorated provided us with optimum relaxing. Excellent home-made Swedish food completed the ideal conditions for our first meeting. The two days and half gathered scientists that already worked together in a prior network, and new colleagues of either academic or companies. We began our program with a presentation of the network by our coordinator, Maria Masucci, appreciated by all for her energy and enthusiasm. We were introduced to the subtleties and managing principles of European Networks of Excellence by RUBICON’s scientific officer, Indridi Benediktsson, who answered all our questions. The partner's presentations (15 min each) were grouped along our three main work-packages (WP), "components", "fate" and "functions" of ubiquitin and ubiquitin-like proteins, and it was very clear that work in the three WPs will be closely interconnect. Many efforts will be devoted at identification of new substrates of known Ubiquitin E3 ligases (mammalian E6AP or plant Cul4 ubiquitome) (Scheffner and Genschik), SUMO (Melchior, Hay, Dejean), or Nedd8 E3 ligases (Gordon). These proteomic searches will be conducted by different strategies in different model organisms ranging from fission yeast, plant, mammalian cells, and even the entire animal (mice). Systematic characterization of the monoubiquitome in mammals (Di Fiore), important in trafficking, potentially resulting from multiple E3 ubiquitin ligases’s activities will also be performed. These approaches will be critically dependent on excellent specialized mass spectroscopy core facility platform, also important for deciphering the type of ubiquitin chains received by specific ubiquitylated substrates, potentially interacting with specific ubiquitin binding proteins (Scheffner, Jentsch, Israel, Strous, Ben-Neriah, Haguenauer-Tsapis). The tools (antibodies, ubiquitin chains etc) developed by BioMol will be of critical importance for this part of the project. In the same field, the mode of recognition of the substrates will be of constant interest, notably in the case of sumoylation, where structural analysis of sumoylation sites will be conducted with development of a peptide library, coupled to crystallization of modified or unmodified SUMO targets (Pepscan, Sixma, Melchior). After identification of general proteasome inhibitors, important for research and clinical use, identification of precise E3 inhibitors is of critical clinical importance. Such a search will be performed by two of the associated companies in the case of E6AP (Scheffner, Cytomics), or POSH (Proteologics). The first and traditional function of ubiquitylation is to target proteins for degradation by the proteasome. The presence in a target of Gly-Ala repeat, as observed in Epstein-Barr virus, leads to only partial proteolysis, and depending of the stimulus, polarized intestinal cells display sensibility or complete resistance to proteolysis of IKB and NFKB. Searching the actors involved in these two types of proteasome resistance will be the objective of Masucci and Ben-Neriah, respectively. PCNA, provides a unique example of a DNA-binding protein that undergoes all possible types of post-translational modifications (mono or polyubiquitylation of different types, sumoylation), in relationship with its functions in DNA repair. It will be critical to identify the physical interactors of the various modified forms of PCNA (Jentsch). Ubiquitin is involved in several aspects of signaling pathways (Notch, NFKB, TNF etc.), by modifications leading to activation of kinases, or ubiquitin-dependent degradation of proteins prior nuclear import of transcription factors. Several groups will try to identify the actors involved in these pathways (E3s, DUBs, substrates, partners) (Israel, Bernards, Ben Neriah, Strous), with specific emphasis on ubiquitin and Ubl specific proteases (DUBs), these still ill-defined actors in the ubiquitin field. The siRNA library enabling inhibition of multiple DUBs and Ubl-proteases and subsequent high-content imaging screens developed by Bernards’s lab will constitute powerful tools, notably in order to identify the potential DUB(s) involved in Notch signaling, where the involvement of multiple E3s is known but DUBs still missing (Bernards, Israel). Two specific functions of ubiquitin in intracellular trafficking will be studied. ERAD clears the ER from unfolded proteins. ERAD involves several E2s, E3s, Ubiquitin-binding proteins, and chaperones. Finding new ERAD components, identifying which actors are involved in ERAD of specific soluble and membrane-bound proteins, and ordering the successive events will be the objectives of several yeast groups (Sommer, Wolf). Ubiquitin is involved at various steps of the endocytic pathway, by modification of either endocytic cargoes, or actors of the endocytic machinery, identification of the targets, E3s and their partners, involved ubiquitin-binding proteins, themselves sometimes ubiquitylated , will be the objective of several groups (Strous, Di Fiore, Haguenauer-Tsapis). Our network will thus cover many aspects of the ubiquitin and Ubl field, and we will all largely benefit from many possible intellectual and technical interactions. The presentation of all shared core facilities (genomic, imaging, structural, antibody/protein facilities, chemical libraries), presented at the end of the meeting, raised a strong interest, and many demands were already formulated. We still need to find an optimal solution for our future proteomics core-facility. After collective discussions in order to agree on a potential scientific advisory board, we all left the meeting with a very positive view of our network. In addition to the collaborations already planned, the possibility of informal discussions during the meeting already led to the initiation of new collaborative projects. We all look forward to our first plenary meeting that will be held in November 2006.

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Haguenauer-Tsapis Rosine (Principal Investigator / Rosine Haguenauer-Tsapis's Group)

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