Translational Homeostasis via the mRNA Cap-Binding Protein, elF4E

Translational control of gene expression plays a key role in many biological processes. Consequently, the activity of the translation apparatus is under tight homeostatic control. elF4E, the mRNA 5' cap-binding protein, facilitates cap-dependent translation and is a major target for translational control. elF4E activity is controlled by a family of repressor proteins, termed 4E-binding proteins (4E-BPs). Here, we describe the surprising finding that despite the importance of elF4E for translation, a drastic knockdown of elF4E caused only minor reduction in translation. This conundrum can be explained by the finding that 4E-BP1 is degraded in elF4E-knock-down cells. Hypophosphorylated 4E-BP1, which binds to elF4E, is degraded, whereas hyperphosphorylated 4E-BP1 is refractory to degradation. We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of elF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination.