title: Mixed lineage kinase-3 stabilizes and functionally cooperates with TRIBBLES-3 to compromise mitochondrial integrity in cytokine-induced death of pancreatic beta cells.
abstract: Mixed lineage kinases (MLKs) have been implicated in cytokine signaling as well as in cell death pathways. Our studies show that MLK3 is activated in leukocyte-infiltrated islets of non-obese diabetic mice and that MLK3 activation compromises mitochondrial integrity and induces apoptosis of beta cells. Using an ex vivo model of islet-splenocyte co-culture, we show that MLK3 mediates its effects via the pseudokinase TRB3, a mammalian homolog of Drosophila Tribbles. TRB3 expression strongly coincided with conformational change and mitochondrial translocation of BAX. Mechanistically, MLK3 directly interacted with and stabilized TRB3, resulting in inhibition of Akt, a strong suppressor of BAX translocation and mitochondrial membrane permeabilization. Accordingly, attenuation of MLK3 or TRB3 expression each prevented cytokine-induced BAX conformational change and attenuated the progression to apoptosis. We conclude that MLKs compromise mitochondrial integrity and suppress cellular survival mechanisms via TRB3-dependent inhibition of Akt.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92037, USA.
authors.forename: Rohan K
authors.initials: RK
authors.lastname: Humphrey
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Newcomb
authors.forename: Shu-Mei A
authors.initials: SM
authors.lastname: Yu
authors.forename: Ergeng
authors.initials: E
authors.lastname: Hao
authors.forename: Doris
authors.initials: D
authors.lastname: Yu
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Keyong
authors.initials: K
authors.lastname: Du
authors.forename: Ulupi S
authors.initials: US
authors.lastname: Jhala
mesh_terms: D000328:Adult; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C474830:TRB3 protein, mouse