Zhao Wenming, Modak Ayan, Ross Susan R
Department of Microbiology and Immunology, University of Illinois Chicago College of Medicine, Chicago, Illinois, United States of America.
PLoS Pathog. 2025 Apr 1;21(4):e1013045. doi: 10.1371/journal.ppat.1013045. eCollection 2025 Apr.
APOBEC3 family proteins are critical host factors that counteract and prevent the replication of retroviruses and other viruses through cytidine deamination. Human APOBEC3 proteins inactivate 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 murine retroviruses 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 murine leukemia virus (MLV) 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.
载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3）家族蛋白是重要的宿主因子，可通过胞嘧啶脱氨作用对抗并阻止逆转录病毒和其他病毒的复制。人类APOBEC3蛋白通过向病毒基因组引入致死性突变使HIV-1失活。相比之下，小鼠APOBEC3虽然保留了功能性胞嘧啶脱氨酶活性，但不会诱导鼠类逆转录病毒的DNA超突变。小鼠APOBEC3不能有效使鼠类逆转录病毒脱氨的原因仍不清楚。在本研究中，我们发现死亡框解旋酶DHX15与小鼠APOBEC3相互作用并抑制其脱氨活性。DHX15独立于其与APOBEC3的结合被包装进鼠白血病病毒（MLV）病毒粒子中。此外，敲低DHX15可抑制MLV复制，并导致前病毒DNA中出现更多的G到A突变。最后，敲低DHX15可诱导鼠细胞中的DNA损伤，这表明它在表达小鼠APOBEC3蛋白的细胞中对维持基因组完整性发挥作用。
