PMC:1626108 / 33915-36045 JSONTXT

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For example, the combination of the CLD of RanBP2 with several subunits of the 19S cap of the proteasome [14], and of its neighboring internal repeat, W1W2/IR with the E3-ubiquitin ligase, parkin [20], and the E2 SUMO-1-conjugating protein, Ubc9 [15] may contribute to the down-regulation of HKI by 26S proteasome-mediated proteolysis and modulation of the molecular and subcellular partitioning of these partners. In this regard, it will be interesting to probe whether parkin also causes deficits in HKI in dopaminergic neurons, since parkin was reported to modulate RanBP2 turnover [20], and parkin loss-of-function also causes energy and growth deficits [26–29,42]. These data add a new dimension to the complexity of the regulation of the glycolytic pathway, in particular in the CNS, where glycolysis plays a major role in supplying energy and where the proteasome machinery may play a critical role in modulating components of the energy supply machinery [43]. This is further evidenced by the presence of genetic modifiers in RanBP2+/−mice on a mixed genetic background that compensates for deficits in RanBP2 and deregulation of its partners in glucose/energy homeostasis as observed in the coisogenic line. The presence of such compensatory mechanisms is also supported by the identification of a quantitative trait locus, which encompasses RanBP2, and modifies the expression of diabetes-related phenotypes 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