Abstract
BackgroundThe human myxovirus resistance 2 (Mx2/MxB) protein was originally found to regulate cytoplasmic-nuclear transport but was recently reported to restrict HIV-1 replication by binding to HIV-1 capsid (CA), preventing uncoating, the nuclear import of pre-integration complex (PIC) and viral DNA integration. This work explores the mechanisms of MxB-mediated HIV-1 inhibition.ResultsWe demonstrated that MxB represses NUP358-mediated PIC nuclear import and HIV-1 replication. Moreover, MxB’s effects on PIC nuclear import and HIV-1 replication depend critically on cofactor cleavage and polyadenylation specificity factor subunit 6 (CPSF6). MxB binds nucleoporin NUP358, blocks NUP358-CA interaction, thereby impeding the nuclear import of HIV-1 PIC with CPSF6 binding to PIC. More intriguingly, CPSF6’s role in nuclear import depends on MxB, being a facilitator of HIV-1 nuclear import on its own, but becoming an inhibitor when MxB is present.ConclusionsOur work establishes that MxB impedes the NUP358-mediated HIV-1 nuclear import and viral replication cooperatively with CPSF6.
Highlights
The human myxovirus resistance 2 (Mx2/MxB) protein was originally found to regulate cytoplasmicnuclear transport but was recently reported to restrict Human immunodeficiency virus 1 (HIV-1) replication by binding to HIV-1 capsid (CA), preventing uncoating, the nuclear import of pre-integration complex (PIC) and viral DNA integration
2-long terminal repeat (LTR) circular DNA and integrated DNA were decreased in cells stably expressing MxB, though the second strand transfer products of Late Reverse transcriptase (RT) did not differ as compared to the control cells
To investigate how MxB affects HIV-1 nuclear import, we first examined the association of MxB with one of the most important nucleoporins, NUP358, which is responsible for recruiting HIV-1 PIC at the cytoplasmic side of nuclear pore complex (NPC) during nuclear import [24]
Summary
The human myxovirus resistance 2 (Mx2/MxB) protein was originally found to regulate cytoplasmicnuclear transport but was recently reported to restrict HIV-1 replication by binding to HIV-1 capsid (CA), preventing uncoating, the nuclear import of pre-integration complex (PIC) and viral DNA integration. Human Myxovirus resistance protein 2 (Mx2/MxB), a member of the dynamin-like large GTPases that belong to the dynamin superfamily, was originally found to regulate cell-cycle progression and cytoplasmic-nuclear transport [1], but recently was demonstrated to inhibit the infection of various viruses, including HIV-1 [2,3,4], Herpesviruses [5, 6], HTNV [7], HCV [8], HBV [9] and other lentiviruses such as SIV, EIAV and FIV [2]. Several studies further demonstrated that HIV-1 preferentially relies on NUP358 to enter the nuclei of host cells [23, 25,26,27]
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