p21-Activated Kinase 4 Signaling Promotes Japanese Encephalitis Virus-Mediated Inflammation in Astrocytes

Abstract

Japanese encephalitis virus (JEV) targets central nervous system, resulting in neuroinflammation with typical features of neuronal death along with hyper activation of glial cells. Exploring the mechanisms responsible for the JEV-caused inflammatory response remains a pivotal area of research. In the present study, we have explored the function of p21-activated kinase 4 (PAK4) in JEV-mediated inflammatory response in human astrocytes. The results showed that JEV infection enhances the phosphorylation of PAK4 in U251 cells and mouse brain. Knockdown of PAK4 resulted in decreased expression of inflammatory cytokines that include tumor necrosis factor alpha, interleukin-6, interleukin-1β, and chemokine (C-C motif) ligand 5 and interferon β upon JEV infection, suggesting that PAK4 signaling promotes JEV-mediated inflammation. In addition, we found that knockdown of PAK4 led to the inhibition of MAPK signaling including ERK, p38 MAPK and JNK, and also resulted in the reduced nuclear translocation of NF-κB and phosphorylation of AP-1. These results demonstrate that PAK4 signaling actively promotes JEV-mediated inflammation in human astrocytes via MAPK-NF-κB/AP-1 pathway, which will provide a new insight into the molecular mechanism of the JEV-induced inflammatory response.

P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

“…These findings are novel in that there is only one study (35) reporting p38 activation affecting the activity of Group-II PAKs, and no studies reporting ERK activation per se alters PAK4 activity. Except for this study (35), in all other reports ERK (46,56,64,65,78) and p38 (28,32) activation is a downstream signaling event of PAK4 activation.…”

Pathogenicity and virulence of Japanese encephalitis virus: Neuroinflammation and neuronal cell damage

“…The JEV-induced expression of CCR2 on the surface of microglia is positively correlated with the neurotoxic microglia activation phenotype and subsequent inflammatory response [ 23 ]. Regarding the astrocytic immune mechanisms, JEV infection of cultured human or mouse astrocytes is known to trigger PAK4/MAPK-NF-κB/AP-1 [ 24 ] and ROS/Src/PDGFR/PI3K/Akt/MAPK/AP-1 [ 25 ] signaling pathways, respectively, to enhance the production of inflammatory cytokines. The interaction between JEV subgenomic RNA (ssRNA) and TLR7, as assessed by co-immunoprecipitation, negatively regulated type-I IFN and inflammatory response in cultured neurons and mice brain tissues [ 26 ].…”

PAK6 promotes cervical cancer progression through activation of the Wnt/β‑catenin signaling pathway

“…PAK4 suppression downregulated the expression levels of cyclin A1, D1 and E1, and upregulated the expression levels of p27 and p21, leading to G1 arrest in pancreatic cancer cells (30). Moreover, PAK4 knockdown reduced the activation of several pro-survival pathways, including the NF-κB, ERK and JNK signaling pathways (31,32). Similar to PAK4, PAK5 knockdown delayed the G0/G1 phase of the human gastric cancer, liver cancer and glioma cell cycle, thereby inhibiting cell proliferation (33).…”