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

In late 2019, a sudden rise in respiratory-related disease
cases in China triggered the identification of its
source as a novel corona virus, termed severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2). The disease
caused by novel SARS-CoV-2 is named as CO-
VID-19 by the World Health Organization [1]. The culprit
virus belongs to the Coronaviridae family of coronaviruses
that caused 2 other outbreaks, namely, severe acute
respiratory syndrome (SARS) in 2002 [2] and Middle East
respiratory syndrome in 2012 [3]. As the survival of every
virus depends on its host cell, the understanding of cellular
functions such as signaling pathways that are essential
for viral replication may be suitable to define targets
for antiviral therapy and pave the way toward effective
drugs against essential cellular activities supporting viral
replication [4]. In this regard, we have focused on the Raf/
MEK/ERK signaling pathway, which is probably one of
the most well-known signal transduction pathways
among biologists because of its implication in a wide variety
of cellular functions such as cell proliferation, cell
cycle arrest, and apoptosis [5]. The mechanism of this
pathway is initiated by G protein-coupled receptors,
which leads to the phosphorylation of downstream molecules
and activates the serine threonine kinase Raf (dual
specificity kinase MEK and MAPK/ERK). 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]. For example, herpes simplex type-1 virus-induced
activation of the Raf/MEK/ERK pathway is used
for cytoskeleton rearrangement during entry [9], JC polyomavirus
requires ERK activation for viral transcription
[10], and influenza A virus hijacks Raf/MEK/ERK activity
for efficient viral ribonucleoprotein export [11, 12].
Ebola virus glycoprotein-induced cytotoxicity