title: Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic β cell death.
abstract: 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. 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 β cells, an early step in the progression toward β cell death. These studies suggest a novel mechanism for MLK3 activation and provide new clues for therapeutic intervention in promoting β cell survival.
authors.affiliation: Pediatric Diabetes Research Center, University of California, San Diego, School of Medicine, La Jolla, California 92037, USA.
authors.forename: Rohan K
authors.initials: RK
authors.lastname: Humphrey
authors.forename: Shu Mei A
authors.initials: SM
authors.lastname: Yu
authors.forename: Aditi
authors.initials: A
authors.lastname: Bellary
authors.forename: Sumati
authors.initials: S
authors.lastname: Gonuguntla
authors.forename: Myra
authors.initials: M
authors.lastname: Yebra
authors.forename: Ulupi S
authors.initials: US
authors.lastname: Jhala
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D019281:Dimerization; D056945:Hep G2 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology*; D008239:Lysine / Q000737:chemistry*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C490666:MAPK8IP1 protein, human; C490665:Mapk8ip protein, mouse