Swaminath Sharmada, Mendes Marisa, Zhang Yipeng, Remick Kaleigh A, Mejia Isabel, Güereca Melissa, Te Velthuis Aartjan J W, Russell Alistair B
Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
Nat Commun. 2025 Feb 22;16(1):1875. doi: 10.1038/s41467-025-57092-2.
Influenza A virus encodes conserved promoter sequences. Using minimal replication assays-transfections with viral polymerase, nucleoprotein, and a genomic template-these sequences were identified as 13nt at the 5' end of the genomic RNA (U13) and 12nt at the 3' end (U12). Other than the fourth 3' nucleotide, the U12 and U13 sequences are identical between all eight RNA molecules of the segmented influenza A genome. However, individual segments can exhibit different dynamics during infection. Influenza NS2, which modulates transcription and replication differentially between genomic segments, may provide an explanation. Here, we assess how internal sequences of two genomic segments, HA and PB1, contribute to NS2-dependent replication and map such interactions down to individual nucleotides in PB1. We find that the expression of NS2 significantly alters sequence requirements for efficient replication beyond the identical U12 and U13 sequences, providing a potential mechanism for segment-specific replication dynamics across the influenza genome.
甲型流感病毒编码保守的启动子序列。通过最小复制试验——用病毒聚合酶、核蛋白和基因组模板进行转染——这些序列被确定为基因组RNA 5'端的13个核苷酸（U13）和3'端的12个核苷酸（U12）。除了第4个3'核苷酸外，甲型流感病毒分段基因组的所有8个RNA分子之间的U12和U13序列是相同的。然而，在感染过程中，各个片段可能表现出不同的动态变化。流感病毒NS2蛋白在基因组片段之间对转录和复制进行差异调节，这可能对此提供了解释。在此，我们评估了两个基因组片段HA和PB1的内部序列如何促进NS2依赖的复制，并将这种相互作用定位到PB1中的单个核苷酸。我们发现，NS2的表达显著改变了除相同的U12和U13序列之外高效复制的序列要求，为流感病毒基因组中片段特异性复制动态变化提供了一种潜在机制。
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