Adenovirus RIDα regulates endosome maturation by mimicking GTP-Rab7

he small guanosine triphosphatase Rab7 regulates late endocytic trafficking. Rab7- interacting lysosomal protein ( RILP) and oxysterol- binding protein related protein 1L ( ORP1L) are guanosine triphosphate ( GTP) - Rab7 effectors that instigate minus end - directed microtubule transport. We demonstrate that RILP and ORP1L both interact with the group C adenovirus protein known as receptor internalization and degradation alpha ( RID alpha), which was previously shown to clear the cell surface of several membrane proteins, including the epidermal growth factor receptor and Fas ( Carlin, C. R., A. E. Tollefson, H. A. Brady, B. L. Hoffman, and W. S. Wold. 1989. Cell. 57: 135 - 144; Shisler, J., C. Yang, B. Walter, C. F. Ware, and L. R. Gooding. 1997. J. Virol. 71: 8299 - 8306). RID alpha localizes to endocytic vesicles but is not homologous to Rab7 and is not catalytically active. We show that RID alpha compensates for reduced Rab7 or dominant- negative ( DN) Rab7( T22N) expression. In vitro, Cu2+ binding to RID alpha residues His75 and His76 facilitates the RILP interaction. Site- directed mutagenesis of these His residues results in the loss of RID alpha-RILP interaction and RIDa activity in cells. Additionally, expression of the RILP DN C-terminal region hinders RIDa activity during an acute adenovirus infection. We conclude that RID alpha coordinates recruitment of these GTP- Rab7 effectors to compartments that would ordinarily be perceived as early endosomes, thereby promoting the degradation of selected cargo.