Abstract
ABSTRACTThe postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It is known that the formation of repressive chromatin at the 5′-LTR of HIV-1 proviral DNA impedes viral transcription by blocking the recruitment of positive transcription factors. How the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. Elucidation of which chromatin reassembly factor mediates the reorganization of chromatin is likely to facilitate the understanding of the host’s modulation of HIV-1 transcription and latency. Here we revealed that “Sad1 and UNC84 domain containing 2” (SUN2), an inner nuclear membrane protein, maintained the repressive chromatin and inhibited HIV LTR-driven transcription of proviral DNA through an association with lamin A/C. Specifically, lamin A/C tethered SUN2 to the nucleosomes 1 and 2 of the HIV-1 5′-LTR to block the initiation and elongation of HIV-1 transcription. SUN2 knockdown converted chromatin to an active form and thus enhanced the phosphorylation of RNA polymerase II and its recruitment to the 5′-LTR HIV-1 proviral DNA, leading to reactivation of HIV-1 from latency. Conversely, the exogenous factors such as tumor necrosis factor alpha (TNF-α) induced reactivation, and the replication of HIV-1 led to the disassociation between SUN2 and lamin A/C, suggesting that disruption of the association between SUN2 and lamin A/C to convert the repressive chromatin to the active form might be a prerequisite for the initiation of HIV-1 transcription and replication. Together, our findings indicate that SUN2 is a novel chromatin reassembly factor that helps to maintain chromatin in a repressive state and consequently inhibits HIV-1 transcription.
Highlights
The postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome
To further determine the mechanism of Sad1 and UNC84 domain containing 2” (SUN2)-mediated inhibition of HIV-1 transcription, we investigated whether SUN2 could inhibit LTR activity by cotransfection of HEK293T cells with the SUN2-expressing pcDNA3.1 plasmid along with a luciferase reporter driven by the full-length LTR promoter from HIV-1NL4-3 and treated the transfected cells with or without tumor necrosis factor alpha (TNF-␣), which is known to enhance LTR activity [40]
We revealed a pivotal role of SUN2 as a novel chromatin reassembly factor in modulating chromatin structure and HIV-1 transcription
Summary
The postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It has been known that the formation of repressive chromatin at the 5=-LTR of HIV-1 proviral DNA impedes viral transcription and maintains viral latency, but how the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. We performed in-depth virological and cell biological studies and discovered that an inner nuclear membrane protein, SUN2, is a novel chromatin reassembly factor that maintains repressive chromatin and modulates HIV-1 transcription and latency: targeting SUN2 may lead to new strategies for HIV cure. The specific regulation of chromatin organization, by either regulating the expression of chromatin reassembly factors and their associations with repressive nucleosome or altering the histone epigenetic modifications, modulates HIV-1 proviral 5=-LTR activity and viral latency. Mutations in genes encoding LINC complex proteins are with cardiac and skeletal myopathies [22, 23]
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