FBSコロキウム 354回ユビキチン生物学研究室

Exploring the Role of HOIL-1 E3 Ligase in Clearance of Aggregates

The linear ubiquitin chain assembly complex (LUBAC) is an E3 ligase complex crucial for catalyzing linear ubiquitin chains, essential in immune signaling and various biological processes, including protein quality control. Comprising two RBR-type E3 ligases, HOIP and HOIL-1, along with the accessory protein SHARPIN, LUBAC orchestrates the formation of oxyester-branched linear polyubiquitin heterotypic chains. While HOIP is responsible for catalyzing linear ubiquitin chains, HOIL-1 has been implicated in generating oxyester ubiquitin linkages. Recent studies have highlighted the role of HOIL-1 in preventing polyglucosan aggregate formation by monoubiquitinating glycogen via oxyester linkage. HOIL-1 deficiency leads to the accumulation of toxic polyglucosan bodies in cardiac muscle and brain tissues, resulting in cardiomyopathy and cognitive impairment, respectively. However, the precise mechanism involved in HOIL-1-mediated aggregate removal remains unclear. We find that in the presence of a catalytically inactive HOIL-1 mutant, aggregate-prone proteins accumulate within cells. Interestingly, LUBAC components coexist in the aggregate fractions. In mouse embryonic fibroblasts (MEFs)-derived from HOIL-1 mutant mice, puromycin-induced p62-positive puncta persist longer in comparison to wildtype MEFs, indicating a defect in aggregate clearance. In this talk, I aim to elucidate the role of HOIL-1 in aggregate formation and removal, and the possible molecular mechanisms underlying this phenomenon.