Abstract
Viral accessory proteins hijack host cell E3 ubiquitin ligases to antagonize innate/intrinsic defenses and thereby provide a more permissive environment for virus replication. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr reprograms CRL4DCAF1 E3 to antagonize select postreplication DNA repair enzymes, but the significance and role of these Vpr interactions are poorly understood. To gain additional insights, we performed a focused screen for substrates of CRL4DCAF1 E3 reprogrammed by HIV-1 Vpr among known postreplication DNA repair proteins and identified exonuclease 1 (Exo1) as a novel direct HIV-1 Vpr target. We show that HIV-1 Vpr recruits Exo1 to the CRL4DCAF1 E3 complex for ubiquitination and subsequent proteasome-dependent degradation and that Exo1 levels are depleted in HIV-1-infected cells in a Vpr-dependent manner. We also show that Exo1 inhibits HIV-1 replication in T cells. Notably, the antagonism of Exo1 is a conserved function of main group HIV-1 and its ancestor Vpr proteins in the simian immunodeficiency virus from chimpanzee (SIVcpz) lineage, further underscoring the relevance of our findings. Overall, our studies (i) reveal that HIV-1 Vpr extensively remodels the cellular postreplication DNA repair machinery by impinging on multiple repair pathways, (ii) support a model in which Vpr promotes HIV-1 replication by antagonizing select DNA repair enzymes, and (iii) highlight the importance of a new class of restrictions placed on HIV-1 replication in T cells by the cellular DNA repair machinery.IMPORTANCE HIV-1 polymerase reverse transcribes the viral RNA genome into imperfectly double-stranded proviral DNA, containing gaps and flaps, for integration into the host cell chromosome. HIV-1 reverse transcripts share characteristics with cellular DNA replication intermediates and are thought to be converted into fully double-stranded DNA by cellular postreplication DNA repair enzymes. Therefore, the finding that the HIV-1 accessory protein Vpr antagonizes select postreplication DNA repair enzymes that can process HIV-1 reverse transcripts has been surprising. Here, we show that one such Vpr-antagonized enzyme, exonuclease 1, inhibits HIV-1 replication in T cells. We identify exonuclease 1 as a member of a new class of HIV-1 restriction factors in T cells and propose that certain modes of DNA "repair" inhibit HIV-1 infection.
Highlights
Viral accessory proteins hijack host cell E3 ubiquitin ligases to antagonize innate/intrinsic defenses and thereby provide a more permissive environment for virus replication
We set up a targeted screen aiming to identify novel proteins that are involved in postreplication DNA repair and are directed for proteasome-mediated degradation via Human immunodeficiency virus type 1 (HIV-1) Vpr bound to CLR4DCAF1 E3
We show that Vpr proteins of HIV-1 and its ancestor simian immunodeficiency virus from chimpanzee (SIVcpz) lineage reprogram CRL4DCAF1 E3 to antagonize the postreplication DNA repair enzyme exonuclease 1 (Exo1)
Summary
Viral accessory proteins hijack host cell E3 ubiquitin ligases to antagonize innate/intrinsic defenses and thereby provide a more permissive environment for virus replication. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr reprograms CRL4DCAF1 E3 to antagonize select postreplication DNA repair enzymes, but the significance and role of these Vpr interactions are poorly understood. The human immunodeficiency virus type 1 (HIV-1) accessory proteins Vpr, Vif, and Vpu reprogram cellular E3 ubiquitin ligases to direct key host cell proteins that restrict HIV infection for proteasome-dependent degradation. Several tentative target proteins of the Vpr-CRL4DCAF1 E3 were recently identified, four of which are bona fide Vpr-recruited substrates [11,12,13] The latter includes proteins identified by unbiased screens and have well-established roles in postreplication DNA repair, such as uracil-DNA glycosylase 2 (UNG2) [14], MUS81 [15], and helicase like transcription factor (HLTF) [16, 17], or in epigenetic control of gene expression, such as ten eleven translocation methylcytosine dioxygenase 2 (Tet2) [11], which, notably, is involved in DNA damage response and repair [18]. HLTF is a DNA helicase which catalyzes strand reversal at damaged replication forks [24]
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