Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation.
The PDZ proteins such as hDLG, hScrib and MAGIs function as the membrane-associated protein scaffolds and have been shown to interact with the high-risk human papillomavirus (HPV) E6s. In this report, we identify a Golgi-associated PDZ protein, cystic fibrosis transmembrane regulator-associated ligand (CAL) as a cellular target of HPV16 E6 by the proteomic approach. The carboxy-terminal PDZ-binding motif of HPV16 E6 specifically interacts with the PDZ domain of CAL, and the interaction enhances proteasome-mediated degradation of CAL. HPV16 E6 interacts with CAL more strongly and degrades it better than HPV18 E6 owing to the more compatible PDZ-binding motif. CAL is ubiquitinated by the E6/E6-associated protein (E6AP) complex or by E6AP alone, albeit less efficiently, which indicates that it could be a normal target of E6AP. Although it downregulates CAL at the transcript level, small interfering RNA-induced depletion of HPV16 E6 in Caski cells stabilizes CAL at the protein level, suggesting that HPV16 E6 mediates the proteasomal degradation of CAL in HPV-positive cervical cancer cells. HPV16 E6 may tightly regulate the vesicular trafficking processes by interacting with CAL, and such a modification can contribute to the development of cervical cancer.
Jeong
K W
KW
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Kim
H-Z
HZ
Kim
S
S
Kim
Y S
YS
Choe
J
J
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D000077614:Golgi Matrix Proteins; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C068651:E6 protein, Human papillomavirus type 16; C434484:GOPC protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D025801:Ubiquitin; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex