title: Multiple phosphorylation sites at the C-terminus regulate nuclear import of HCMV DNA polymerase processivity factor ppUL44.
abstract: The processivity factor of human cytomegalovirus DNA polymerase, phosphoprotein ppUL44, is essential for viral replication. During viral infection ppUL44 is phosphorylated by the viral kinase pUL97, but neither the target residues on ppUL44 nor the effect of phosphorylation on ppUL44's activity are known. We report here that ppUL44 is phosphorylated when transiently expressed in mammalian cells and coimmunoprecipitates with cellular kinases. Of three potential phosphorylation sites (S413, S415, S418) located upstream of ppUL44's nuclear localization signal (NLS) and one (T427) within the NLS itself, protein kinase CK2 (CK2) specifically phosphorylates S413, to trigger a cascade of phosphorylation of S418 and S415 by CK1 and CK2, respectively. Negative charge at the CK2/CK1 target serine residues facilitates optimal nuclear accumulation of ppUL44, whereas negative charge on T427, a potential cyclin-dependent 1 phosphorylation site, strongly decreases nuclear accumulation. Thus, nuclear transport of ppUL44 is finely tuned during viral infection through complex phosphorylation events.
authors: Department of Hematology and Oncology Lorenzo e Ariosto Seràgnoli, University of Bologna, Medical School, Bologna, Italy. gualtiero.alvisi@unipd.it
authors: Gualtiero
authors: G
authors: Alvisi
authors: Oriano
authors: O
authors: Marin
authors: Gregory
authors: G
authors: Pari
authors: Manuela
authors: M
authors: Mancini
authors: Simone
authors: S
authors: Avanzi
authors: Arianna
authors: A
authors: Loregian
authors: David A
authors: DA
authors: Jans
authors: Alessandro
authors: A
authors: Ripalti
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000472:pathogenicity*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D010766:Phosphorylation; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C072217:ICP36 protein, Cytomegalovirus; D014764:Viral Proteins