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

The Journal of biological chemistry

PubMedID: 23172226

Humphrey RK, Yu SM, Bellary A, Gonuguntla S, Yebra M, Jhala US. Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic ß cell death. J Biol Chem. 2013;288(4):2428-40.
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 ß cell death. In an effort to identify mechanisms that regulate MLK3 activity in ß cells, we discovered that IL-1ß 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. Inability to ubiquitinate MLK3, or the presence of A20, an upstream Lys-63-linked deubiquitinase, strongly curtailed the ability of MLK3 to affect the proapoptotic translocation of BAX in cytokine-stimulated pancreatic ß cells, an early step in the progression toward ß cell death. These studies suggest a novel mechanism for MLK3 activation and provide new clues for therapeutic intervention in promoting ß cell survival.