טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKoltun Bella
SubjectThe Roles of Degringolade (Dgrn), a SUMO Targeted
Ubiquitin Ligase, in Embryonic Development and
in Innate Immunity of Drosophila
DepartmentDepartment of Medicine
Supervisor Professor Amir )Oryan )Orian
Full Thesis textFull thesis text - English Version


Abstract

Crosstalk between post-transcriptional modifications by ubiquitin and ubiquitin-like proteins is emerging as a new layer of gene expression regulation. In part, this crosstalk impacts directly transcription factor (TF) localization, their ability to recruit co-factors, and TF activity. In this regard, recent work from our laboratory suggest that SUMO-Targeted Ubiquitin Ligase (STUbL) connects SUMOylation with ubiquitylation, and regulates selective co-repressor recruitment during development. One example is Degringolade (Dgrn), the sole STUbL in Drosophila. Dgrn connects the SUMO and the ubiquitin pathways as it binds to SUMOylated proteins and targets them for ubiquitylation. In this study I investigated the role(s) of Dgrn during transcriptional activation. First, I focused on its role in gene activation during early embryonic development, and specifically on the formation of embryonic exes. I found that Dgrn is required for proper establishment of the termini and Dorsal-Ventral axis. For example, embryos derived from dgrn null females fail to express key target genes of the Torso and Toll signaling pathways, which are required for terminal patterning and Dorso-Ventral specification respectively. Second, and using the adult immune system as a model, I characterized the role of Dgrn in the activation of genes required to cope with infection. I found that adult dgrn mutant flies are immune compromised, sensitive to various pathogenic agents, and fail to express immune-related anti-microbial peptides. Moreover, my results suggest a role for Dgrn in local gut response to infection. Using oral feeding assays and monitoring local gut homeostasis I established a role for Dgrn in post-infection stem-cell regeneration via the Notch pathway. In addition my results also suggest a role for Dgrn in hemocyte proliferation/melanization, that is key for coping with invading pathogens. Here I found that over-expression of Dgrn results in the formation of melanotic tumors.  Taken together, my results suggest a role for Dgrn as part of a molecular machinery essential for transcriptional activation during early embryonic development and host defense in Drosophila.