Viral oncoprotein-induced mislocalization of select PDZ proteins disrupts tight junctions and causes polarity defects in epithelial cells.
The development of human cancers is frequently associated with a failure of epithelial cells to form tight junctions and to establish proper apicobasal polarity. Interestingly, the oncogenic potential of the adenovirus E4-ORF1 protein correlates with its binding to the cellular PDZ proteins MUPP1, MAGI-1, ZO-2 and SAP97, the first three of which assemble protein complexes at tight junctions. Given that E4-ORF1 sequesters these three PDZ proteins in the cytoplasm of fibroblasts, we postulated that E4-ORF1 would inhibit tight junction formation in epithelial cells. Providing further support for this idea, we identified MUPP1-related PATJ, a key component of the tight junction-associated CRB3-PALS1-PATJ polarity complex, as a new PDZ-protein target for both the E4-ORF1 and high-risk human papillomavirus type 18 E6 oncoproteins. Moreover, in epithelial cells, E4-ORF1 blocked the tight junction localization of PATJ and ZO-2, as well as their interacting partners, and disrupted both the tight junction barrier and apicobasal polarity. These significant findings expose a direct link between the tumorigenic potential of E4-ORF1 and inactivation of cellular PDZ proteins involved in tight junction assembly and polarity establishment.
Latorre
Isabel J
IJ
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Roh
Michael H
MH
Frese
Kristopher K
KK
Weiss
Robert S
RS
Margolis
Ben
B
Javier
Ronald T
RT
D017504:Adenovirus E4 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells; D005136:Eye Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D062725:Tight Junction Proteins; D019108:Tight Junctions / Q000378:metabolism* / Q000821:virology*
D017504:Adenovirus E4 Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C101120:E4 protein, Adenovirus 9; C052603:E6 protein, Human papillomavirus type 18; D005136:Eye Proteins; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; C107903:PATJ protein, human; D062725:Tight Junction Proteins