The ubiquitin system is a reversible post-translational modification system that regulates protein functions in numerous ways. A distinctive feature of the system is its diversity in modification styles. Ubiquitin is conjugated to the proteins as ubiquitin chains in most cases. The ubiquitin linkages forming the chains are generally amido bonds between C-terminal carboxyl groups and amino groups in lysine residues and N-terminal methionine of ubiquitin. However, recent findings suggested that the linkages can be generated via ester bonds in some cases.
Linear ubiquitin chains formed via N-terminal methionine, which we discovered in 2006, are specifically generated by the LUBAC (linear ubiquitin chain assembly complex) ligase complex. LUBAC-mediated linear ubiquitination does not lead to protein degradation but rather contributed to immune responses. Recent studies identified that dysregulated linear ubiquitination is causative to immune disorders. Profound impairment of linear ubiquitination due to the mutations in LUBAC subunits is causative to autoinflammatory diseases with immunodeficiency. Mutations in OTULIN, a specific deubiquitinating enzyme cleaving linear linkages, can also lead to autoinflammatory diseases. In contrast, elevated LUBAC activity is associated with a representative systemic autoimmune disease, systemic lupus erythematosus (SLE). Recent progress in LUBAC in autoimmune disorders will be discussed.