Small GTPase Rab12 regulates transferrin receptor degradation: Implications for a novel membrane trafficking pathway from recycling endosomes to lysosomes.

Plasma membrane receptor proteins play a key role in signal transduction and nutrient uptake, thereby controlling quality of receptor proteins is one of the most important issues in cellular logistics. After endocytosis, receptor proteins are generally delivered to lysosomes for degradation or recycled back to the plasma membrane for recycling. Transferrin receptor (TfR) is a well-known representative of recycling receptor proteins, which are traveled between plasma membrane and recycling endosomes. Although the molecular mechanism of the TfR recycling pathway has been extensively investigated in the literature, almost nothing is known about its degradation mechanism. We have recently shown that small GTPase Rab12 and its upstream activator Dennd3 regulate the constitutive degradation of TfR without modulating a conventional endocytic degradation pathway or TfR recycling pathway. Our findings suggest that Rab12 regulates membrane trafficking of TfR from recycling endosomes to lysosomes. In this addendum, we discuss the physiological significance of TfR degradation and the fate of determination of TfR (recycling or degradation).