HA Triggers the Switch from MEK1 SUMOylation to Phosphorylation of the ERK Pathway in Influenza A Virus-Infected Cells and Facilitates Its Infection

Abstract

Several post-translational modifications in host cells are hijacked by pathogens to facilitate their propagation. A number of components of the influenza virus have been reported to be modified by small ubiquitin-like modifier (SUMO) proteins during infection. We hypothesized that the MAPK/ERK pathway could be modified by SUMO1 because the SUMOylation of MEK1 was quickly eliminated after influenza A virus infection. We identified host cell MEK1 as a target of SUMO1 through LC/MS/MS, and enhanced MEK1 SUMOylation inhibited the infection of the virus, while inhibition of host cell MEK1 SUMOylation facilitated virus propagation. Further investigation demonstrated that the MAPK/ERK pathway is downregulated by MEK1 SUMOylation, which is inhibited by influenza virus infection. Furthermore, membrane accumulation of hemagglutinin promoted MEK1 phosphorylation and gradually abrogated the MEK1 SUMOylation. Taken together, we report a possible mechanism in which HA may trigger the ERK pathway in influenza A virus-infected cells as the switch from MEK1 SUMOylation to phosphorylation, facilitating virus infection.

Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host

“…Recent studies of cellular metabolic processes [ 97 , 98 ] and post-transcriptional protein modification [ 99 , 100 ] identified additional approaches used by viruses to evade host immune responses [ 101 ], and to facilitate optimal replication [ 102 ].…”

Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways

“…In contrast to many other signaling events in IAV-infected cells, it is not activated by viral RNA (vRNA) sensing via RIG-I but rather is induced by accumulation of newly produced viral hemagglutinin (HA) in lipid rafts in the membrane of infected cells (Marjuki et al, 2006 ). Furthermore, it was recently shown that the presence of HA triggers the switch from MEK1 SUMOylation to an activating phosphorylation leading to the downstream activation of ERK1/2 (Wang et al, 2017 ). Thus, the cascade is implicated to control temporal coordination of virus particle assembly (Marjuki et al, 2006 ).…”

The Two Sides of the Same Coin—Influenza Virus and Intracellular Signal Transduction

“…This appears to induce the formation of lipid rafts, which serve as signaling platforms for protein kinase C (PKC)-dependent Raf/MEK/ERK activation, presumably by bringing monomeric receptor molecules in close proximity to each other. Further findings showed that HA triggers a switch from MEK1 SUMOylation to activation of the ERK pathway, thereby enhancing the activity of the cascade (Wang et al 2017).…”