ITCH is regulated by MAPK8. MAPK8 regulates JUNB protein turnover by MAPK8-dependent phosphorylation of ITCH and a subsequent conformational change in ITCH. This mechanism is discrete from the direct activation of Jun family transcription factors by direct phosphorylation. ITCH serves as a paradigm for our understanding of the regulation of the ubiquitylation machinery by direct protein phosphorylation of its components. Importantly, this regulatory process controls the balance of Th2 cytokine secretion by negatively regulating JUNB levels and Interleukin 4 transcription.