Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1.
In models of type 1 diabetes, cytokines induce pancreatic beta-cell death by apoptosis. This process seems to be facilitated by a reduction in the amount of the islet-brain 1/JNK interacting protein 1 (IB1/JIP1), a JNK-scaffold with an anti-apoptotic effect. A point mutation S59N at the N terminus of the scaffold, which segregates in diabetic patients, has the functional consequence of sensitizing cells to apoptotic stimuli. Neither the mechanisms leading to IB1/JIP1 down-regulation by cytokines nor the mechanisms leading to the decreased capacity of the S59N mutation to protect cells from apoptosis are understood. Here, we show that IB1/JIP1 stability is modulated by intracellular calcium. The effect of calcium depends upon JNK activation, which primes the scaffold for ubiquitination-mediated degradation via the proteasome machinery. Furthermore, we observe that the S59N mutation decreases IB1/JIP1 stability by sensitizing IB1/JIP1 to calcium- and proteasome-dependent degradation. These data indicate that calcium influx initiated by cytokines mediates ubiquitination and degradation of IB1/JIP1 and may, therefore, provide a link between calcium influx and JNK-mediated apoptosis in pancreatic beta-cells.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D017931:DNA Primers; D015536:Down-Regulation; D006801:Humans; D006868:Hydrolysis; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C490666:MAPK8IP1 protein, human; C110528:Mapk8ip1 protein, rat; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D015534:Trans-Activators; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002118:Calcium