Late activation of theRaf/MEK/ERKpathway is required for translocation of the respiratory syncytial virusFprotein to the plasma membrane and efficient viral replication

Abstract

Activation of the Raf/MEK/ERK cascade is required for efficient propagation of several RNA and DNA viruses, including human respiratory syncytial virus (RSV). In RSV infection, activation of the Raf/MEK/ERK cascade is biphasic. An early induction within minutes after infection is associated with viral attachment. Subsequently, a second activation occurs with, so far, unknown function in the viral life cycle. In this study, we aimed to characterise the role of Raf/MEK/ERK-mediated signalling during ongoing RSV infection. Our data show that inhibition of the kinase MEK after the virus has been internalised results in a reduction of viral titers. Further functional investigations revealed that the late-stage activation of ERK is required for a specific step in RSV replication, namely, the secretory transport of the RSV fusion protein F. Thus, MEK inhibition resulted in impaired surface accumulation of the F protein. F protein surface expression is essential for efficient replication as it is involved in viral filament formation, cell fusion, and viral transmission. In summary, we provide detailed insights of how host cell signalling interferes with RSV replication and identified the Raf/MEK/ERK kinase cascade as potential target for novel anti-RSV strategies.

Emerging Regulatory Roles of Dual-Specificity Phosphatases in Inflammatory Airway Disease

“…This altered the cellular distribution of SH, increasing localization in the golgi, implying that phosphorylation of SH may be necessary for transport through the secretory pathway and thus, viral assembly [54]. A similar role was proposed for ERK, as treatment of A549 cells with U0126 reduced surface expression of the viral F protein [53].…”

“…The roles of the MAPK pathways in RSV replication have also been investigated. Inhibition of p38 or ERK diminished levels of viral RNA and progeny release in A549 cells [52,53]. In both cases, this was thought to be due to impaired transport of viral proteins through the secretory pathway.…”

Porcine deltacoronavirus activates the Raf/MEK/ERK pathway to promote its replication

“…Hence, it is not surprising that viruses hijack cellular signaling cascades, which in turn modulate and contribute to viral survival. Indeed, a number of viruses have been shown to inherit the Raf/MEK/ERK pathway to complete their replication cycle (Cai et al, 2007;Kim and Lee, 2015;Lee and Lee, 2010;Lim et al, 2005;Marjuki et al, 2006;Moser and Schultz-Cherry, 2008;Preugschas et al, 2019;Rodríguez et al, 2014;Schümann and Dobbelstein, 2006;Wang et al, 2006;Wei and Liu, 2009;Zampieri et al, 2007). However, the importance of the ERK signaling pathway in PDCoV replication has not been investigated thus far.…”

SARS-CoV-2 and the Possible Role of Raf/MEK/ERK Pathway in Viral Survival: Is This a Potential Therapeutic Strategy for COVID-19?

“…ERK phosphorylates various substrates, transforms the signals, and follows different functions in cells [ 6 ]. Hence, it is not surprising that several DNA and RNA viruses inherit this pathway, apart from an initial activation upon viral attachment, for various steps in the viral life cycle [ 7 ]. Consequently, the kinetic of pathway activation is highly dynamic [ 8 ].…”