Abstract
The p12 protein of the murine leukemia virus (MLV) is a constituent of the pre-integration complex (PIC) but its function in this complex remains unknown. We developed an imaging system to monitor MLV PIC trafficking in live cells. This allowed the visualization of PIC docking to mitotic chromosomes and its release upon exit from mitosis. Docking occurred concomitantly with nuclear envelope breakdown and was impaired for PICs of viruses with lethal p12 mutations. Insertion of a heterologous chromatin binding module into p12 of one of these mutants restored PICs attachment to the chromosomes and partially rescued virus replication. Capsid dissociated from wild type PICs in mitotic cells but remained associated with PICs harboring tethering-negative p12 mutants. Altogether, these results explain, in part, MLV restriction to dividing cells and reveal a role for p12 as a factor that tethers MLV PIC to mitotic chromosomes.
Highlights
To integrate, reverse transcribed retroviral genomes are imported from the cytoplasm to the chromosomes as part of a pre-integration complex (PIC)
Retroviruses, including the murine leukemia virus (MLV), reverse transcribe their RNA genome to a DNA copy, which travels from the cytoplasm to the nucleus as part of a ‘pre-integration complex’ (PIC), to integrate into cellular chromosomes
The viral p12 protein is a constituent of the MLV PIC, but its function in this complex has remained unknown
Summary
Reverse transcribed retroviral genomes are imported from the cytoplasm to the chromosomes as part of a pre-integration complex (PIC). Differences in retrovirus PIC trafficking influence their ability to infect resting and/or dividing cells. Lentiviruses, including the human immunodeficiency virus (HIV), infect both dividing and resting cells. Simple oncoretroviruses, such as murine leukemia viruses (MLV), are restricted to dividing cells [1,2,3,4]. The HIV PIC is capable of entering the nucleus through the nuclear pore complexes, allowing integration in chromosomes of resting cells. The MLV PIC is thought to get access to the chromosomes only during mitosis, upon nuclear envelope (NE) disassembly, as inferred from correlating kinetics of cell division and integration [3]
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