Abstract
Viruses exploit the host cell machinery for their own profit. To evade innate immune sensing and promote viral replication, HIV type 1 (HIV-1) subverts DNA repair regulatory proteins and induces G2/M arrest. The preintegration complex of HIV-1 is known to traffic along microtubules and accumulate near the microtubule-organizing center. The centrosome is the major microtubule-organizing center in most eukaryotic cells, but precisely how HIV-1 impinges on centrosome biology remains poorly understood. We report here that the HIV-1 accessory protein viral protein R (Vpr) localized to the centrosome through binding to DCAF1, forming a complex with the ubiquitin ligase EDD-DYRK2-DDB1DCAF1 and Cep78, a resident centrosomal protein previously shown to inhibit EDD-DYRK2-DDB1DCAF1 Vpr did not affect ubiquitination of Cep78. Rather, it enhanced ubiquitination of an EDD-DYRK2-DDB1DCAF1 substrate, CP110, leading to its degradation, an effect that could be overcome by Cep78 expression. The down-regulation of CP110 and elongation of centrioles provoked by Vpr were independent of G2/M arrest. Infection of T lymphocytes with HIV-1, but not with HIV-1 lacking Vpr, promoted CP110 degradation and centriole elongation. Elongated centrioles recruited more γ-tubulin to the centrosome, resulting in increased microtubule nucleation. Our results suggest that Vpr is targeted to the centrosome where it hijacks a ubiquitin ligase, disrupting organelle homeostasis, which may contribute to HIV-1 pathogenesis.
Highlights
Viruses exploit the host cell machinery for their own profit
viral protein R (Vpr) binds to Cep78 and EDD-DYRK2-DDB1DCAF1 and localizes to the centrosome
Vpr binds to the WD40 domain of DCAF1 [15, 51], whereas Cep78 binds to the acidic domain of DCAF1 [37]
Summary
Viral protein R; TERT, telomerase reverse transcriptase; HA, hemagglutinin; Ub, ubiquitin; DDR, DNA damage response; DAPI, 4Ј,6-diamidino-2-phenylindole; ROI, region of interest. Vpr has been observed to disrupt certain protein interactions at the centrosome [48] and induce centrosome amplification and multipolar spindle formation [49, 50], suggesting that this viral protein is capable of exerting an effect on the centrosome either directly or indirectly. Despite these observations, the extent to which Vpr modulates different aspects of centrosome biology and the underlying mechanisms have not been studied in detail
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