DHX15 inhibits mouse APOBEC3 deamination activity

APOBEC3 family proteins are critical host proteins that counteract and prevent the replication
of retroviruses and other viruses through cytidine deamination. Human APOBEC3G inactivates
HIV-1 through the introduction of lethal mutations to viral genomes. In contrast, mouse
APOBEC3 does not induce DNA hypermutation of murine retroviruses, although it retains
functional cytidine deaminase activity. Why mouse APOBEC3 does not effectively deaminate
MLV is still unknown. In this study, we found that the dead box helicase DHX15 interacts with
mouse APOBEC3 and inhibits its deamination activity. DHX15 was packaged into virions
independent of its binding with APOBEC3. Moreover, DHX15 knockdown inhibited MLV
replication and resulted in more G-to-A mutations in proviral DNA. Finally, DHX15 knockdown
induced DNA damage in murine cells, suggesting that it plays a role in preserving genome
integrity in cells expressing mouse APOBEC3 protein.

APOBEC3家族蛋白是至关重要的宿主蛋白，通过胞嘧啶脱氨作用，拮抗并阻止逆转录病毒及其他病毒复制。人源APOBEC3G通过向病毒基因组引入致死性突变，使HIV-1失活。然而，小鼠APOBEC3并未引起小鼠逆转录病毒的DNA高突变，尽管它仍保留了功能性的胞嘧啶脱氨酶活性。为何小鼠APOBEC3不能有效脱氨MLV，这一问题尚无明确答案。在本研究中，我们发现死盒螺旋酶DHX15与小鼠APOBEC3相互作用，并抑制其脱氨活性。DHX15的包装与它对APOBEC3的结合无关。此外，DHX15敲低抑制了MLV的复制，并在前病毒DNA中导致更多的G到A突变。最终，DHX15敲低在鼠细胞中诱导DNA损伤，这表明它在维持表达小鼠APOBEC3蛋白的细胞基因组完整性方面发挥着作用。