Abstract
The nuclear export receptor CRM1 is an important regulator involved in the shuttling of various cellular and viral RNAs between the nucleus and the cytoplasm. HIV-1 Rev interacts with CRM1 in the late phase of HIV-1 replication to promote nuclear export of unspliced and single spliced HIV-1 transcripts. However, other cellular factors involved in the CRM1-dependent viral RNA nuclear export remain largely unknown. Here, we demonstrate that ANP32A and ANP32B mediate the export of unspliced or partially spliced viral mRNA via interactions with Rev and CRM1. We found that a double, but not single, knockout of ANP32A and ANP32B significantly decreased the expression of gag protein. Reconstitution of either ANP32A or ANP32B restored the viral production equally. Disruption of both ANP32A and ANP32B expression led to a dramatic accumulation of unspliced viral mRNA in the nucleus. We further identified that ANP32A and ANP32B interact with both Rev and CRM1 to promote RNA transport. Our data strongly suggest that ANP32A and ANP32B play an important role in the Rev-CRM1 pathway, which is essential for HIV-1 replication, and our findings provide a candidate therapeutic target for host defense against retroviral infection.
Highlights
The nuclear export receptor CRM1 is an important regulator involved in the shuttling of various cellular and viral RNAs between the nucleus and the cytoplasm
It has been reported that foamy virus nuclear RNA export depends on the HuR and CRM1 pathways in which ANP32A and ANP32B act as necessary cofactors [24]
The results showed that single knockout of either ANP32A or ANP32B has no impact on HIV type 1 (HIV-1) gag expression, whereas a significant decrease in p24 expression in the cytosol and cell culture supernatant was observed in the double KO cell line (DKO) cells compared with WT, ANP32A single knockout cell line ⌬ANP32A (AKO), and BKO cells (Fig. 1C)
Summary
MRNA is presumably transported into the cytoplasm mediated by the TAP/NXF1 pathway to translate the regulatory proteins Rev, Nef, and Tat. A number of host factors (including Matrin-3, DDX1, DDX21, DDX3, DDX5, MOV10, Sam, and CBP80) have been reported to interact with Rev and RRE and help viral mRNA export from the nucleus to the cytoplasm (14 –23). Most of these factors have not been identified as interacting with CRM1. Whether ANP32A/B are involved in the Rev-dependent CRM1 pathways for HIV-1 unspliced RNA nuclear export is unknown. We investigated the functions of two proteins that interact with CRM1, ANP32A, and ANP32B, during the export of HIV-1 unspliced mRNA from the nucleus to the cytoplasm. Our work showed that ANP32A and ANP32B play similar roles and contribute to CRM1-dependent RNA export by interacting with both Rev and CRM1, enhancing viral production and replication
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