Immunometabolic role of metabolic enzyme PANK4 in regulation of TLR7/9-mediated innate immunity

Innate immune responses are intimately linked to cellular metabolism, yet the molecular connections between metabolic reprogramming and antiviral defense remain incompletely defined. Here, we identify PANK4, an atypical member of pantothenate kinase family involved in coenzyme A (CoA) biosynthesis, as an unexpected regulator of RNA virus including influenza virus pathogenesis. Unlike other pantothenate kinases, PANK4 lacks canonical kinase activity but has been implicated in metabolic regulation. We show that influenza virus infection, in conjunction with pantothenic acid, induces PANK4 expression, which promotes viral replication by enhancing glucose uptake and glycolytic activity. Loss of PANK4 curtailed viral replication, reduced expression of glycolytic regulators, and heightened host antiviral defenses. Mechanistically, PANK4 interacts with UNC93B1 to suppress TLR7 and TLR9 mediated cytokine responses, thereby acting as a negative regulator of nucleic acid–sensing innate immune pathways in various cell-types. Furthermore, viral proteins NS1 and PB1 exploit PANK4 to amplify replication and immune evasion.