Phosphorylation of JIP4 at S730 Presents Antiviral Properties against Influenza A Virus Infection

Abstract

Influenza A virus (IAV) is the causative agent of flu disease that results in annual epidemics and occasional pandemics. IAV alters several signaling pathways of the cellular host response in order to promote its replication. Therefore, some of these pathways can serve as targets for novel anti-viral agents. Here, we show that c-Jun NH2-terminal kinase (JNK)-interacting protein (JIP) 4 is dynamically phosphorylated in IAV infection. Lack of JIP4 resulted in higher virus titers with significant differences in viral protein and mRNA accumulation as early as within the first replication cycle. In accordance, decreased IAV titers and protein accumulation was observed during overexpression of JIP4. Strikingly, the anti-viral function of JIP4 does neither originate from a modulation of JNK or p38 MAPK pathways, nor from altered expression of interferons or interferon-stimulated genes, but rather from a direct reduction of viral polymerase activity. Furthermore, interference of JIP4 with IAV replication seems to be linked to phosphorylation of the serine at position 730 that is sufficient to impede with the viral polymerase. Collectively, we provide evidence that JIP4, a host protein modulated in IAV infection, exhibits anti-viral properties that are dynamically controlled by its phosphorylation at S730. Importance Influenza A virus (IAV) infection is a world health concern and current treatment options encounter high rates of resistance. Our group investigates host pathways modified in IAV infection as promising new targets. Host protein JIP4 is dynamically phosphorylated in IAV infection. JIP4 absence resulted in higher virus titers, viral protein and mRNA accumulation within the first replication cycle. Accordingly, decreased IAV titers and protein accumulation was observed during JIP4 overexpression. Strikingly, the anti-viral function of JIP4 does neither originate from a modulation of JNK or p38 MAPK pathways, nor from altered expression of interferons or interferon-stimulated genes, but rather from a reduction in viral polymerase activity. Interference of JIP4 with IAV replication is linked to phosphorylation of serine 730. We provide evidence that JIP4, a host protein modulated in IAV infection, exhibits anti-viral properties that are dynamically controlled by its phosphorylation at S730.

Sperm-Associated Antigen 9 Promotes Influenza A Virus-Induced Cell Death via the c-Jun N-Terminal Kinase Signaling Pathway

“…SPAG9 has been reported to affect the replication of IAV ( 20 ). Therefore, to exclude the possibility that different cell death rates may be caused by distinct viral replication levels, a high multiplicity of infection (MOI) of 2 was used to maximize cell death independent of differences in viral replication.…”

SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling

“…Among JIP proteins, SPAG9 or JIP4 (also known as MAPK8IP4) is involved in MAPK signaling pathway to regulate cellular activities 71 . Del Sarto et al recently have identified an increase of phosphorylaton at Ser730 in JIP4 after Influenza A virus infection 72 . Similarly, other work has recently described that this phosphorylation promotes cell death via c-jun kinase signaling pathway 73 .…”

“…after Influenza A virus infection 72 . Similarly, other work has recently described that this phosphorylation promotes cell death via c-jun kinase signaling pathway 73 .…”

SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling

“…Among JIP proteins, SPAG9 or JIP4 (also known as MAPK8IP4) is involved in MAPK signaling pathway to regulate cellular activities (79). Del Sarto et al recently have identified an increase of phosphorylaton at Ser730 in JIP4 after Influenza A virus infection (80). Similarly, other work has recently described that this phosphorylation promotes cell death via c-jun kinase signaling pathway (81).…”

“…Del Sarto et al. recently have identified an increase of phosphorylaton at Ser730 in JIP4 after Influenza A virus infection ( 80 ). Similarly, other work has recently described that this phosphorylation promotes cell death via c-jun kinase signaling pathway ( 81 ).…”