Regulation of CFTR-associated ligand by human papillomavirus E6 protein and a ubiquitin ligase, E6AP = 파필로마 바이러스 E6 단백질과 유비퀴틴 연결효소 E6AP에 의한 CFTR-결합 리간드의 조절 기작에 관한 연구

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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 HPV E6s. In the present study, we identified a Golgi-associated PDZ protein, CFTR-associated ligand (CAL) as a cellular target of HPV16 E6 by the proteomic approach. HPV16 E6 specifically interacted with the PDZ domain of CAL through the carboxy-terminal PDZ-binding motif, and the interaction caused 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 was highly ubiquitinated by the E6/E6AP complex or by E6AP alone albeit less efficiently. By siRNA-induced depletion of HPV16 E6 in Caski cells, CAL was down-regulated at the transcription level, but was stabilized at the protein level, suggesting that HPV16 E6 mediates the proteasomal degradation of CAL in HPV-positive cervical cancer cells. E6AP alone can bind, destabilize and ubiquitinate CAL independent of E6. In HPV-negative cells, the suppression of E6AP expression increased the protein level of CAL. Taken together, CAL is likely a natural target protein of E6AP and undergoes the E6/E6AP-induced degradation in an HPV-infected state. The E6/E6AP complex may tightly regulate the vesicular trafficking processes by interacting with CAL, and such a modification can contribute to the development of cervical cancer. In addition, the E6AP-mediated regulation of CAL is supposed to be important for understanding the etiology of Angelman syndrome.
Choe, Joon-Horesearcher최준호researcher
한국과학기술원 : 생명과학과,
Issue Date
258107/325007  / 020025874

학위논문(박사) - 한국과학기술원 : 생명과학과, 2006.8, [ vi, 110 p. ]


HPV E6-induced proteasomal degradation of CAL; 파필로마바이러스 E6 단백질에 의한 CFTR 결합 리간드의 분해

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