Open AccessNRIP, a Novel Calmodulin Binding Protein, Activates Calcineurin To Dephosphorylate Human Papillomavirus E2 Protein
Author(s) -
ShangTzen Chang,
YeouPing Tsao,
Chia–Yi Lin,
ShowLi Chen
Publication year - 2011
Publication title -
journal of virology
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.02453-10
Subject(s) - biology , calcineurin , calmodulin binding proteins , calmodulin , human papillomavirus , plasma protein binding , binding protein , oncogene proteins , microbiology and biotechnology , virology , biochemistry , regulation of gene expression , gene , enzyme , medicine , surgery , transplantation
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.