Adenovirus RIDalpha regulates endosome maturation by mimicking GTP-Rab7.
The 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 (RIDalpha), 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). RIDalpha localizes to endocytic vesicles but is not homologous to Rab7 and is not catalytically active. We show that RIDalpha compensates for reduced Rab7 or dominant-negative (DN) Rab7(T22N) expression. In vitro, Cu(2+) binding to RIDalpha residues His75 and His76 facilitates the RILP interaction. Site-directed mutagenesis of these His residues results in the loss of RIDalpha-RILP interaction and RIDalpha activity in cells. Additionally, expression of the RILP DN C-terminal region hinders RIDalpha activity during an acute adenovirus infection. We conclude that RIDalpha coordinates recruitment of these GTP-Rab7 effectors to compartments that would ordinarily be perceived as early endosomes, thereby promoting the degradation of selected cargo.
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Ankur H
AH
Shah
Nicholas L
NL
Cianciola
Jeffrey L
JL
Mills
Frank D
FD
Sönnichsen
Cathleen
C
Carlin
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000256:Adenoviridae / Q000187:drug effects / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D003300:Copper / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011987:Receptors, Steroid; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins; D000098825:Oxysterol Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C491901:FAS protein, human; C423317:RILP protein, human; D011987:Receptors, Steroid; D014764:Viral Proteins; D019014:fas Receptor; D000098825:Oxysterol Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D003300:Copper; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins