Characterization of molecular attributes that influence LINE-1 restriction by all seven human APOBEC3 proteins

Abstract

LINE-1 (L1) is a non-long terminal repeat (LTR) retrotransposon inserted throughout the human genome. APOBEC3 (A3) proteins are part of a network of host intrinsic defenses capable of restricting retroviruses and the replication of L1 retroelements. These enzymes inactivate retroviruses primarily through deamination of single-stranded viral DNA. In contrast, only A3A deaminates L1 DNA, while the other six A3 proteins restrict L1 to varying degrees through yet poorly defined mechanisms. Here we provide further insight into the molecular attributes of L1 restriction by A3 proteins. We specifically investigated the roles of A3 protein oligomerization, interactions with RNA and their binding to the various L1 proteins. Our results show that compromising the ability of A3 proteins to oligomerize or interact with a nucleic acid substrate diminished L1 restriction to varying degrees. However the efficiency of their binding to L1 proteins did not predict restriction or the potency of the restriction.

The Interplay Among HIV, LINE-1, and the Interferon Signaling System

“…Interestingly, by removing genes from the viral genome, they uncovered that both Vif and Vpr are essential for HIV-induced LINE-1 promotion. This result was understandable because the key function of Vif is to induce the degradation of antiviral proteins from the APOBEC3 family ( 116 ), some of which also act as LINE-1 suppressors, as mentioned above ( 96 ). Moreover, Vpr is famous for its high potency in arresting the host cell cycle at the G2/M phage ( 117 ), which subsequently promotes HIV production ( 118 ).…”

“…However, as research has extended to more ISG proteins, it is surprising to observe that many of them inhibit HIV and LINE-1 with alternative mechanisms [please refer to ( 112 ) for additional details]. For example, dNTPase activity is essential for SAMHD1 to suppress HIV replication ( 56 ) but dispensable in SAMHD1-mediated LINE-1 regulation ( 70 , 113 ); moreover, DNA deamination plays a key role in APOBEC3-induced HIV suppression but is not involved in APOBEC3 inhibiting LINE-1, with APOBEC3A as the only exception ( 96 ). There are some possible reasons to explain such phenomena, such as the differences between the replication processes of HIV and LINE-1 and the subcellular localization of restriction factors and HIV/LINE-1 components, while the timing of suppression might be the most important.…”

“…With active copies of LINE-1 already being integrated into the human genome (which is different from the case in exogenous HIV infection), an alternative mechanism is therefore necessary. In fact, APOBEC3 proteins interact with ORF1p and/or ORF2p; consequently, compromising the formation/stability/functionality of LINE-1 RNP might be the mechanism by which APOBEC3 proteins suppress LINE-1 replication ( 96 ). Notably, such phenomena also indicate that the differences between HIV and LINE-1 are in fact significant enough for host factors to distinguish the two and that it is possible to design an intervention approach specifically targeting HIV without interfering with LINE-1 and its ability to maintain innate immune activation.…”

Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells

“…The APOBEC3 (A3) superfamily (including A3C, A3D and A3H) proteins play important roles in antiviral immunity related to retroviruses, retroviral elements and RNA editing enzymes that involve RT-activity regulation, but also in tumor cell growth and cell cycle control [66], [67], [68], [69]. Concerning retrotransposons, hypomethylation of L1-RNP genomic copies was shown to be associated with increased APOBEC-mRNA expression.…”

Antiretroviral APOBEC3 Cytidine Deaminases Alter HIV-1 Provirus Integration Site Profiles

“…(Catalog #11100) 14 . NL4-3-ΔVif/ ΔEnv-eGFP was pseudotyped with Vesicular Stomatitis Virus-G protein (VSV-G) (pMDG) as previously described 21,86 . pcDNA 3.1 (Invitrogen) was used as an empty vector control for transfection and all A3 expressing plasmids have been described previously 21,86 .…”