Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors.
Human parvovirus B19 (B19V) is the only human pathogenic parvovirus. It causes a wide spectrum of human diseases, including fifth disease (erythema infectiosum) in children and pure red cell aplasia in immunocompromised patients. B19V is highly erythrotropic and preferentially replicates in erythroid progenitor cells (EPCs). Current understanding of how B19V interacts with cellular factors to regulate disease progression is limited, due to a lack of permissive cell lines and animal models. Here, we employed a recently developed primary human CD36(+) EPC culture system that is highly permissive for B19V infection to identify cellular factors that lead to cell cycle arrest after B19V infection. We found that B19V exploited the E2F family of transcription factors by downregulating activating E2Fs (E2F1 to E2F3a) and upregulating repressive E2Fs (E2F4 to E2F8) in the primary CD36(+) EPCs. B19V nonstructural protein 1 (NS1) was a key viral factor responsible for altering E2F1-E2F5 expression, but not E2F6-E2F8 expression. Interaction between NS1 and E2F4 or E2F5 enhanced the nuclear import of these repressive E2Fs and induced stable G₂ arrest. NS1-induced G₂ arrest was independent of p53 activation and increased viral replication. Downstream E2F4/E2F5 targets, which are potentially involved in the progression from G₂ into M phase and erythroid differentiation, were identified by microarray analysis. These findings provide new insight into the molecular pathogenesis of B19V in highly permissive erythroid progenitors.
Wan
Zhihong
Z
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892-1652, USA.
Zhi
Ning
N
Wong
Susan
S
Keyvanfar
Keyvan
K
Liu
Delong
D
Raghavachari
Nalini
N
Munson
Peter J
PJ
Su
Su
S
Malide
Daniela
D
Kajigaya
Sachiko
S
Young
Neal S
NS
D021581:Active Transport, Cell Nucleus; D018955:CD36 Antigens / Q000032:analysis; D002453:Cell Cycle; D002454:Cell Differentiation; D002478:Cells, Cultured; D050684:E2F Transcription Factors / Q000502:physiology*; D050704:E2F4 Transcription Factor / Q000502:physiology; D050700:E2F5 Transcription Factor / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000821:virology; D006801:Humans; D016732:Parvovirus B19, Human / Q000472:pathogenicity*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000502:physiology; D014779:Virus Replication
D018955:CD36 Antigens; D050684:E2F Transcription Factors; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D050700:E2F5 Transcription Factor; C092558:E2F5 protein, human; C106202:NS1 protein, parvovirus; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins