Ubiquitin (Ub) is a small modifier that labels proteins in a highly specific manner. Like phosphorylation, modification of proteins by Ub is prevalent in the majority of cellular processes. An increasing number of distinct functions have been assigned to different types of ubiquitin modifications (monoUb and different Lys-linked chains). Moreover, aberrations in the ubiquitin system underlie many disease states, including cancer, inflammatory, immune and metabolic disorders as well as neurodegeneration. The most recently described physiological ubiquitin modification is the linear ubiquitin chain, in which ubiquitin monomers are conjugated via Met-Gly linkages. We have found that linear ubiquitin chains bind specifically to the NEMO adaptor molecule, an event critical for the proper regulation of NF-ºB signaling (Rahighi, 2009). Here we propose to use a multidisciplinary strategy to study the role of linear ubiquitination in the NF-ºB pathway, autophagy, apoptosis and DNA repair and how these changes can impact on disease states such as inflammation and cancer development. Scientific objectives are: " Characterize the components of linear ubiquitination: E3 ligases, specific substrates and domains recognizing linear ubiquitin chains " Elucidate the in vivo role of linear ubiquitination in the regulation of the NF-ºB pathway, apoptosis and DNA repair. " Reveal the molecular basis for the connections between linear ubiquitination and selective autophagy " Identify elements in the linear ubiquitin network as potential drug targets " Generate transgenic mouse models of inflammatory diseases and cancer " Develop system and computational biology approaches to assess the global role of linear ubiquitination in cellular proteome