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APOBEC3 Interference during Replication of Viral Genomes.

Willems L, Gillet NA - Viruses (2015)

Bottom Line: Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission.In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well-conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes.In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), B34, 1 avenue de L'Hôpital, Sart-Tilman Liège 4000, Belgium. luc.willems@ulg.ac.be.

ABSTRACT
Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well-conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes. In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity. Understanding the mechanisms involved reveals new prospects for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus

LINE-1 retrotransposons are targeted by APOBEC3s. After transcription, the LINE-1 mRNA is transported into the cytoplasm. After translation, the ORF1- and ORF2-encoded proteins associate with the LINE-1 RNA and form a ribonucleoprotein (RNP) complex. The LINE-1 RNP enters the nucleus, where the ORF2p endonuclease domain cleaves the chromosomal DNA. After cleavage, the 3′-hydroxyl is used by the LINE-1 reverse transcriptase to synthesize a cDNA of LINE-1. This target-site-primed reverse transcription typically results in the insertion of a 5′-truncated LINE-1 element into a new genomic location. Different APOBEC3s-dependent mechanisms control LINE-1 retrotransposition: (1) in the cytoplasm, A3C interacts with and redirects the L1-RNP into P-bodies for degradation; (2) in the nucleus, A3C inhibits reverse transcriptase processing while A3A mutates the minus strand LINE-1 DNA.
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viruses-07-02757-f003: LINE-1 retrotransposons are targeted by APOBEC3s. After transcription, the LINE-1 mRNA is transported into the cytoplasm. After translation, the ORF1- and ORF2-encoded proteins associate with the LINE-1 RNA and form a ribonucleoprotein (RNP) complex. The LINE-1 RNP enters the nucleus, where the ORF2p endonuclease domain cleaves the chromosomal DNA. After cleavage, the 3′-hydroxyl is used by the LINE-1 reverse transcriptase to synthesize a cDNA of LINE-1. This target-site-primed reverse transcription typically results in the insertion of a 5′-truncated LINE-1 element into a new genomic location. Different APOBEC3s-dependent mechanisms control LINE-1 retrotransposition: (1) in the cytoplasm, A3C interacts with and redirects the L1-RNP into P-bodies for degradation; (2) in the nucleus, A3C inhibits reverse transcriptase processing while A3A mutates the minus strand LINE-1 DNA.

Mentions: About half of the human genome is constituted by repetitive elements. Among them, non-LTR retroelements LINE-1 (long interspersed nuclear element-1), SINE (short interspersed nuclear elements) and Alu are capable of retrotransposition, i.e., inserting a copy of themselves elsewhere in the genome. Since retrotranpositions can be harmful for genome integrity, these events are tightly controlled. In fact, only a small proportion of endogenous retroelements remains active in the germline cells because APOBEC3s protect the host genome from unscheduled retrotransposition (Figure 3). LINE-1 retrotransposition is initiated by transcription of a full-length LINE-1 RNA and translation of ORF1p and ORF2p. These two proteins associate with LINE-1 RNA to form the LINE-1 RiboNucleoProtein (L1 RNP) complex. Upon translocation of L1 RNP into the nucleus, LINE-1 is reverse transcribed and integrated into a new site of the host genome. A3C restricts LINE-1 retrotransposition in a deaminase-independent manner by redirecting and degrading the L1 RNP complex in P-bodies [20]. Within the nucleus, A3C also impairs LINE-1 minus strand DNA synthesis [20]. A3A prevents LINE-1 retrotransposition by deaminating the LINE-1 minus strand DNA [64]. Consistently, RNAse H treatment increases deamination of the LINE-1 minus strand [64].


APOBEC3 Interference during Replication of Viral Genomes.

Willems L, Gillet NA - Viruses (2015)

LINE-1 retrotransposons are targeted by APOBEC3s. After transcription, the LINE-1 mRNA is transported into the cytoplasm. After translation, the ORF1- and ORF2-encoded proteins associate with the LINE-1 RNA and form a ribonucleoprotein (RNP) complex. The LINE-1 RNP enters the nucleus, where the ORF2p endonuclease domain cleaves the chromosomal DNA. After cleavage, the 3′-hydroxyl is used by the LINE-1 reverse transcriptase to synthesize a cDNA of LINE-1. This target-site-primed reverse transcription typically results in the insertion of a 5′-truncated LINE-1 element into a new genomic location. Different APOBEC3s-dependent mechanisms control LINE-1 retrotransposition: (1) in the cytoplasm, A3C interacts with and redirects the L1-RNP into P-bodies for degradation; (2) in the nucleus, A3C inhibits reverse transcriptase processing while A3A mutates the minus strand LINE-1 DNA.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4488724&req=5

viruses-07-02757-f003: LINE-1 retrotransposons are targeted by APOBEC3s. After transcription, the LINE-1 mRNA is transported into the cytoplasm. After translation, the ORF1- and ORF2-encoded proteins associate with the LINE-1 RNA and form a ribonucleoprotein (RNP) complex. The LINE-1 RNP enters the nucleus, where the ORF2p endonuclease domain cleaves the chromosomal DNA. After cleavage, the 3′-hydroxyl is used by the LINE-1 reverse transcriptase to synthesize a cDNA of LINE-1. This target-site-primed reverse transcription typically results in the insertion of a 5′-truncated LINE-1 element into a new genomic location. Different APOBEC3s-dependent mechanisms control LINE-1 retrotransposition: (1) in the cytoplasm, A3C interacts with and redirects the L1-RNP into P-bodies for degradation; (2) in the nucleus, A3C inhibits reverse transcriptase processing while A3A mutates the minus strand LINE-1 DNA.
Mentions: About half of the human genome is constituted by repetitive elements. Among them, non-LTR retroelements LINE-1 (long interspersed nuclear element-1), SINE (short interspersed nuclear elements) and Alu are capable of retrotransposition, i.e., inserting a copy of themselves elsewhere in the genome. Since retrotranpositions can be harmful for genome integrity, these events are tightly controlled. In fact, only a small proportion of endogenous retroelements remains active in the germline cells because APOBEC3s protect the host genome from unscheduled retrotransposition (Figure 3). LINE-1 retrotransposition is initiated by transcription of a full-length LINE-1 RNA and translation of ORF1p and ORF2p. These two proteins associate with LINE-1 RNA to form the LINE-1 RiboNucleoProtein (L1 RNP) complex. Upon translocation of L1 RNP into the nucleus, LINE-1 is reverse transcribed and integrated into a new site of the host genome. A3C restricts LINE-1 retrotransposition in a deaminase-independent manner by redirecting and degrading the L1 RNP complex in P-bodies [20]. Within the nucleus, A3C also impairs LINE-1 minus strand DNA synthesis [20]. A3A prevents LINE-1 retrotransposition by deaminating the LINE-1 minus strand DNA [64]. Consistently, RNAse H treatment increases deamination of the LINE-1 minus strand [64].

Bottom Line: Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission.In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well-conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes.In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), B34, 1 avenue de L'Hôpital, Sart-Tilman Liège 4000, Belgium. luc.willems@ulg.ac.be.

ABSTRACT
Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well-conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes. In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity. Understanding the mechanisms involved reveals new prospects for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus