| Autor: |
Orly, Joseph, Bahat, Assaf, Granot, Zvi, Eimerl, Sarah, Kobiler, Oren, Lu, Bin, Oppenheim, Amos, Suzuki, Carolyn |
| Zdroj: |
Biology of Reproduction; July 2007, Vol. 77 Issue: 1, Number 1 Supplement 1 p171-172, 2p |
| Abstrakt: |
Steroidogenic Acute Regulatory protein (StAR) is a mitochondrial protein essential for massive synthesis of steroid hormones in the adrenal and the gonads. Our studies suggest that following translation, StAR preprotein either associates with the outer mitochondrial membrane to mediate transfer of cholesterol substrate required for steroidgenesis, or it is degraded by the proteasome. Proteasome inhibitors can prevent the turnover of StAR preprotein and other matrix-targeted preproteins. Once imported, excessive accumulation of inactive StAR in the matrix is avoided by a rapid turnover. Unexpectedly, mitochondrial StAR turnover can be inhibited by two proteasome inhibitors, i.e., MG132 and clastolactacystin ?-lactone (lactacystin, IC50= 3 ?M), but not epoxomicin considered to be the most specific inhibitor of the proteasome. To identify the mitochondrial protease involved in StAR degradation we expressed murine StAR in genetically manipulated E. colistrains null for each of the bacterial proteases. We identified Lon as the only protease capable of degrading StAR expressed in these cells. Moreover, in Lon-null bacteria, StAR degradation was fully restored by co-expressing human Lon. The relevance of these studies to degradation of StAR in the mammalian mitochondrial was demonstrated by use of siRNA mediated Lon knockdown experiments, Lon over-expression data, and cell-free assays confirming that that inhibition of StAR or casein degradation by Lon is readily inhibited by the proteasome inhibitors. Further studies are currently carried to unveil the mechanism by which the proteasome inhibitors affect a Ser-Lys (and not catalytic threonine) protease like Lon. (poster) |
| Databáze: |
Supplemental Index |
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