Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1.
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Allaman-Pillet N, Storling J, Oberson A, Roduit R, Negri S, Sauser C, Nicod P, Beckmann JS, Schorderet DF, Mandrup-Poulsen T, Bonny C
Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1.
J Biol Chem. 2003 Dec 5;278(49):48720-6. Epub 2003 Sep 24.
- PubMed ID
- 14507925 [ View in PubMed]
- Abstract
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.