APOBEC3 deaminases induce hypermutation in human papillomavirus 16 DNA upon beta interferon stimulation.
Apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3) proteins are interferon (IFN)-inducible antiviral factors that counteract various viruses such as hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) by inducing cytidine (C)-to-uracil (U) mutations in viral DNA and inhibiting reverse transcription. However, whether APOBEC3 proteins (A3s) can hypermutate human papillomavirus (HPV) viral DNA and exhibit antiviral activity in human keratinocyte remains unknown. Here we examined the involvement of A3s in the HPV life cycle using cervical keratinocyte W12 cells, which are derived from low-grade lesions and retain episomal HPV16 genomes in their nuclei. We focused on the viral E2 gene as a potential target for A3-mediated hypermutation because this gene is frequently found as a boundary sequence in integrated viral DNA. Treatment of W12 cells with beta interferon (IFN-β) increased expression levels of A3s such as A3A, A3F, and A3G and induced C-to-U conversions in the E2 gene in a manner depending on inhibition of uracil DNA glycosylase. Exogenous expression of A3A and A3G also induced E2 hypermutation in W12 cells. IFN-β-induced hypermutation was blocked by transfection of small interfering RNAs against A3G (and modestly by those against A3A). However, the HPV16 episome level was not affected by overexpression of A3A and A3G in W12 cells. This study demonstrates that endogenous A3s upregulated by IFN-β induce E2 hypermutation of HPV16 in cervical keratinocytes, and a pathogenic consequence of E2 hypermutation is discussed.
Department of Molecular Genetics, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Zhe
Z
Wang
Kousho
K
Wakae
Kouichi
K
Kitamura
Satoru
S
Aoyama
Guangyan
G
Liu
Miki
M
Koura
Ahasan M
AM
Monjurul
Iwao
I
Kukimoto
Masamichi
M
Muramatsu
D000071478:APOBEC Deaminases; D001483:Base Sequence; D002460:Cell Line; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D030361:Papillomavirus Infections / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D017354:Point Mutation
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D016899:Interferon-beta; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase