The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion. Unlike wild-type Vpx, the poly-proline tail mutant Vpx is partly defective in enhancing viral infection in macrophages. Our findings suggest that during Vpx evolution, Vpx of the HIV-2/SIVsm/SIVmac lineage is targeted by a CRL4(DCAF1) E3 ligase-independent ubiquitination pathway, and have gained this interesting region, allowing them to maintain nuclear accumulation as part of their adaptation to host cell regulation.

慢病毒辅助蛋白Vpx对于骨髓细胞的病毒感染至关重要，并通过劫持CRL4（DCAF1）E3泛素连接酶来诱导宿主限制因子SAMHD1降解。已经观察到，来自HIV-2和SIVsmm / SIVmac Vpx的序列含有不同于其他SIV Vpx蛋白的多脯氨酸尾。但是，该区域在Vpx函数中的作用是有争议的。在这里，我们发现蛋白酶体依赖的Cpx4（DCAF1）E3连接酶独立的方式在细胞核中缺乏多脯氨酸尾部的Vpx突变体的降解。与野生型Vpx不同，多脯氨酸尾部突变体Vpx在增强巨噬细胞的病毒感染方面有部分缺陷。我们的发现表明，在Vpx进化过程中，HIV-2 / SIVsm / SIVmac谱系的Vpx被CRL4（DCAF1）E3连接酶非依赖性泛素化途径所靶向，