Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic β cell death.

The mixed lineage kinase MLK3 plays a crucial role in compromising mitochondrial integrity and functions as a proapoptotic competence factor in the early stages of cytokine-induced pancreatic β cell death. In an effort to identify mechanisms that regulate MLK3 activity in β cells, we discovered that IL-1β stimulates Lys-63-linked ubiquitination of MLK3 via a conserved, TRAF6-binding peptapeptide motif in the catalytic domain of the kinase. TRAF6-mediated ubiquitination was required for dissociation of inactive monomeric MLK3 from the scaffold protein IB1/JIP1, facilitating the subsequent dimerization, autophosphorylation, and catalytic activation of MLK3.