Mixed Lineage Kinase-3 Stabilizes and Functionally Cooperates with TRIBBLES-3 to Compromise Mitochondrial Integrity in Cytokine-induced Death of Pancreatic Beta Cells |
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| Authors: | Rohan K. Humphrey Christina J. Newcomb Shu-Mei A. Yu Ergeng Hao Doris Yu Stan Krajewski Keyong Du Ulupi S. Jhala |
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| Affiliation: | From the ‡Department of Pediatrics, University of California, San Diego, La Jolla, California 92037.;the §Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and ;the ¶Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111 |
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| 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. |
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| Keywords: | Cell Death Cytokine Action Diabetes Mitochondria Pancreatic Islet Akt BAX MLK3 TRB3 TRIB3 |
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