Development of regulators of the LUBAC ubiquitin ligase that modulate NF-kappaB activation

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NF-kappaB is a family of a transcription factor that involves in various biologcal phenomena including inflammation, immune responses, and cell survival. Abnormal activation NF-kappaB is also known to be related to the pathogenesis of various diseases. Thus, regulation of NF-kappaB is a suitable target of drugs for those diseases. Since we have identified LUBAC-mediated linear polyubiquitination is involved in NF-kappaB activation, we tried to develop the agents that up-regulate or inhibit LUBAC's ligase activity. We then identified a small chemical that inhibits LUBAC-mediated linear polyubiquitination and NF-kappaB actvation. Also, we found that interferon-gamma increases the amount of LUBAC and enhances NF-kappaB actvation.