title: NRIP, a novel calmodulin binding protein, activates calcineurin to dephosphorylate human papillomavirus E2 protein.
abstract: Previously, we found a gene named nuclear receptor interaction protein (NRIP) (or DCAF6 or IQWD1). We demonstrate that NRIP is a novel binding protein for human papillomavirus 16 (HPV-16) E2 protein. HPV-16 E2 and NRIP can directly associate into a complex in vivo and in vitro, and the N-terminal domain of NRIP interacts with the transactivation domain of HPV-16 E2. Only full-length NRIP can stabilize E2 protein and induce HPV gene expression, and NRIP silenced by two designed small interfering RNAs (siRNAs) decreases E2 protein levels and E2-driven gene expression. We found that NRIP can directly bind with calmodulin in the presence of calcium through its IQ domain, resulting in decreased E2 ubiquitination and increased E2 protein stability. Complex formation between NRIP and calcium/calmodulin activates the phosphatase calcineurin to dephosphorylate E2 and increase E2 protein stability. We present evidences for E2 phosphorylation in vivo and show that NRIP acts as a scaffold to recruit E2 and calcium/calmodulin to prevent polyubiquitination and degradation of E2, enhancing E2 stability and E2-driven gene expression.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, 7F, No1, Sec. 1, Jen-Ai Rd., Taipei, Taiwan.
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Chang
authors.forename: Yeou-Ping
authors.initials: YP
authors.lastname: Tsao
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Lin
authors.forename: Show-Li
authors.initials: SL
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019703:Calcineurin / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002148:Calmodulin-Binding Proteins; C501825:DCAF6 protein, human; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D019703:Calcineurin