| First Author | Patel D | Year | 2015 |
| Journal | Mol Metab | Volume | 4 |
| Issue | 4 | Pages | 253-64 |
| PubMed ID | 25830089 | Mgi Jnum | J:223517 |
| Mgi Id | MGI:5649456 | Doi | 10.1016/j.molmet.2015.01.003 |
| Citation | Patel D, et al. (2015) Clic4, a novel protein that sensitizes beta-cells to apoptosis. Mol Metab 4(4):253-64 |
| abstractText | OBJECTIVES: Chloride intracellular channel protein 4 (Clic4) is a ubiquitously expressed protein involved in multiple cellular processes including cell-cycle control, cell differentiation, and apoptosis. Here, we investigated the role of Clic4 in pancreatic beta-cell apoptosis. METHODS: We used betaTC-tet cells and islets from beta-cell specific Clic4 knockout mice (betaClic4KO) and assessed cytokine-induced apoptosis, Bcl2 family protein expression and stability, and identified Clic4-interacting proteins by co-immunoprecipitation and mass spectrometry analysis. RESULTS: We show that cytokines increased Clic4 expression in betaTC-tet cells and in mouse islets and siRNA-mediated silencing of Clic4 expression in betaTC-tet cells or its genetic inactivation in islets beta-cells, reduced cytokine-induced apoptosis. This was associated with increased expression of Bcl-2 and increased expression and phosphorylation of Bad. Measurement of Bcl-2 and Bad half-lives in betaTC-tet cells showed that Clic4 silencing increased the stability of these proteins. In primary islets beta-cells, absence of Clic4 expression increased Bcl-2 and Bcl-xL expression as well as expression and phosphorylation of Bad. Mass-spectrometry analysis of proteins co-immunoprecipitated with Clic4 from betaTC-tet cells showed no association of Clic4 with Bcl-2 family proteins. However, Clic4 co-purified with proteins from the proteasome suggesting a possible role for Clic4 in regulating protein degradation. CONCLUSIONS: Collectively, our data show that Clic4 is a cytokine-induced gene that sensitizes beta-cells to apoptosis by reducing the steady state levels of Bcl-2, Bad and phosphorylated Bad. |
