Role of Ubiquitin E3 ligases in Cell Death and Innate Immune Pathways:

NF-kB pathway is a central regulatory pathway which plays an important role in innate immune system and cell death. Ubiquitination of their component proteins is an important regulatory mechanism for this pathway. Ubiquitination is an important post-translational modification and is completed in three steps: through the sequential action of the ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2, and ubiquitin ligases E3. This process is dynamic and reversible and the rapid removal of ubiquitin from substrates and processing of ubiquitin chains is catalyzed by deubiquitinating enzymes (DUBs). The Ubiquitin E3 ligases are the most diverse component in the Ubiquitination pathway and mediate the attachment of Ubiquitin to the target protein. Thus are responsible for the target specificity. There are two types of E3 ligases, RING and HECT and a not well-characterized E3, U-Box E3 ligases. The RING domain of RING- E3 ligases has a cysteine rich sequence motif that binds to two zinc atoms in a cross- brace manner through seven cysteine and one histidine residue. Recently RING domain proteins have been major focus of several groups. TRAF family members have been well characterized in activation of NF-kB. TRIM family proteins also belong to RING family ubiquitin ligases play important role in antiretroviral immune response however their role in NF-kB and IFN pathway needs to be studied. The U-Box E3 ligases are more recently identified E3- ligases. U-Box contains nearly 70 amino acids and resembles to RING domain but it lack the characteristic zing chelating cysteine and histidine residue of RING domain. There are only few U-Box proteins that have been functionally characterized to date. They play important role in various cellular processes. There are only fewer than 20 U-box proteins predicted in human genome. The focus of present study will be to identify and characterize the role of less studied E3 ligases in NF-kB and cell death pathways.