Genes & genomics · 2026
KIF18A knockdown enhances oxidative phosphorylation, suggesting a metabolic basis for antiviral activity against influenza A virus.
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Kim Hyeong-Rae, Kim Jiwon, Han Dongju, Lee In-Gu, Lim Younghyun, Lee Jeonghyeon, Lee Seungyeon, Hong So-Hee, Seo Young-Jin
Аннотация
BACKGROUND: Influenza A virus (IAV) infection remains a major global health burden, underscoring the need to identify novel host-directed antiviral mechanisms. KIF18A, a kinesin-8 family motor protein, has emerged as a proviral host factor that supports IAV replication, and its pharmacological inhibition suppresses viral infection. However, the transcriptional and metabolic processes underlying this antiviral effect remain incompletely understood.
OBJECTIVE: We aimed to characterize the transcriptional consequences of KIF18A knockdown in IAV-infected cells and identify metabolic pathways potentially associated with its antiviral activity.
METHODS: KIF18A expression was silenced in HEK293T cells by transfection with KIF18A-targeting small interfering RNA. Transcriptomic profiling was performed by RNA sequencing, followed by differential expression and gene set enrichment analyses. Mitochondrial respiratory function was evaluated using the Seahorse XFp Mito Stress assay.
RESULTS: KIF18A knockdown induced extensive transcriptomic remodeling in IAV-infected cells without activating canonical antiviral gene programs. Gene set enrichment analysis of the MSigDB Hallmark collection identified oxidative phosphorylation as the second most significantly enriched pathway. This enrichment was evident in both IAV-infected and non-infected cells, indicating that oxidative phosphorylation upregulation is an intrinsic response to KIF18A depletion rather than a virus-specific effect. Among electron transport chain components, genes encoding Complex Ⅴ ATP synthase subunits exhibited the most consistent upregulation. Concordantly, Seahorse analysis showed significant increases in basal and ATP-linked respiration in siKIF18A cells, without a corresponding increase in proton leak.
CONCLUSION: KIF18A knockdown intrinsically upregulates oxidative phosphorylation and enhances mitochondrial ATP-coupled respiration at both the transcriptional and functional levels, implicating metabolic reprogramming as a candidate mechanism contributing to KIF18A knockdown-mediated antiviral activity against IAV.
OBJECTIVE: We aimed to characterize the transcriptional consequences of KIF18A knockdown in IAV-infected cells and identify metabolic pathways potentially associated with its antiviral activity.
METHODS: KIF18A expression was silenced in HEK293T cells by transfection with KIF18A-targeting small interfering RNA. Transcriptomic profiling was performed by RNA sequencing, followed by differential expression and gene set enrichment analyses. Mitochondrial respiratory function was evaluated using the Seahorse XFp Mito Stress assay.
RESULTS: KIF18A knockdown induced extensive transcriptomic remodeling in IAV-infected cells without activating canonical antiviral gene programs. Gene set enrichment analysis of the MSigDB Hallmark collection identified oxidative phosphorylation as the second most significantly enriched pathway. This enrichment was evident in both IAV-infected and non-infected cells, indicating that oxidative phosphorylation upregulation is an intrinsic response to KIF18A depletion rather than a virus-specific effect. Among electron transport chain components, genes encoding Complex Ⅴ ATP synthase subunits exhibited the most consistent upregulation. Concordantly, Seahorse analysis showed significant increases in basal and ATP-linked respiration in siKIF18A cells, without a corresponding increase in proton leak.
CONCLUSION: KIF18A knockdown intrinsically upregulates oxidative phosphorylation and enhances mitochondrial ATP-coupled respiration at both the transcriptional and functional levels, implicating metabolic reprogramming as a candidate mechanism contributing to KIF18A knockdown-mediated antiviral activity against IAV.