Molecular and regulatory HOXA2 interactions : focus on KPC2 and RCHY1

Hox genes encode transcription factors which fulfill well-documented functions during embryonic development. Regarding the mode of action of these proteins, numerous studies identified Hox-regulated genes and, in some instances, characterized specific target enhancers. However, little data related to Hox-mediated interactions at the protein level is currently available. To better understand the mode of action of Hoxa2, our laboratory started characterizing protein-protein interactions which could be mediated by Hoxa2. During this thesis, nine of these potential Hoxa2 partners were under the scope with a particular focus on two of them, KPC2 and RCHY1. We identified KPC2 as a new HOXA2 regulator and showed that KPC2 modulates HOXA2’s subcellular distribution, relocalizing it to the cytoplasm. Moreover, this relocalization correlates with a decrease in Hoxa2 transcriptional activity. In addition, we demonstrated that the domains of expression of Hoxa2 and Kpc2 partially overlap during mouse embryogenesis which indicates that Hoxa2 might be regulated by Kpc2 in this context. Previous data from the laboratory and results obtained in the present work revealed that HOXA2 fulfills non-transcriptional activities by modulating the proteasomal degradation of RCHY1. Here, we dissected molecular aspects of the HOXA2-RCHY1 interaction, highlighting the mainly nuclear localization of the interaction and revealing the critical involvement of the Hoxa2 homeodomain in its ability to promote RCHY1 degradation. Furthermore, we demonstrated that this ability to modulate RCHY1 stability is evolutionarily conserved for HOXA2 and shared by several but not all HOX proteins. This function could therefore reflect an almost generic and possibly ancestral HOX protein activity.