title: Differential inhibition of long interspersed element 1 by APOBEC3 does not correlate with high-molecular-mass-complex formation or P-body association.
abstract: The human cytidine deaminase APOBEC3G (A3G) and other APOBEC3 proteins exhibit differential inhibitory activities against diverse endogenous retroelements and retroviruses, including Vif-deficient human immunodeficiency virus type 1. The potential inhibitory activity of human APOBEC proteins against long interspersed element 1 (LINE-1) has not been fully evaluated. Here, we demonstrate inhibition of LINE-1 by multiple human APOBEC3 cytidine deaminases, including previously unreported activity for A3DE and A3G. More ancient members of APOBEC, cytidine deaminases AID and APOBEC2, had no detectable activity against LINE-1. A3A, which did not form high-molecular-mass (HMM) complexes and interacted poorly with P bodies, was the most potent inhibitor of LINE-1. A3A specifically recognizes LINE-1 RNA but not the other cellular RNAs tested. However, in the presence of LINE-1, A3A became associated with HMM complexes containing LINE-1 RNA. The ability of A3A to recognize LINE-1 RNA required its catalytic domain and was important for its LINE-1 suppression. Although the mechanism of LINE-1 restriction did not seem to involve DNA editing, A3A inhibited the accumulation of nascent LINE-1 DNA, suggesting interference with LINE-1 reverse transcription and/or integration or intracellular movement of LINE-1 ribonucleoprotein. Thus, association with P bodies or cellular HMM complexes could not predict the potency of APOBEC3 anti-LINE-1 activities. The catalytic domain of APOBEC3 proteins may be important for proper folding and target factors such as RNA or protein interaction in addition to cytidine deamination.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Niewiadomska
authors.forename: Chunjuan
authors.initials: C
authors.lastname: Tian
authors.forename: Lindi
authors.initials: L
authors.lastname: Tan
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Phuong Thi Nguyen
authors.initials: PT
authors.lastname: Sarkis
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D000071478:APOBEC Deaminases; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D003564:Cytidine Deaminase / Q000378:metabolism; D043525:Cytosine Deaminase / Q000378:metabolism*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D046911:Macromolecular Substances / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D011485:Protein Binding; D012313:RNA / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D046911:Macromolecular Substances; D009124:Muscle Proteins; D016601:RNA-Binding Proteins; D012313:RNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C120388:APOBEC2 protein, human; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase