Comprehensive role of SARS-CoV-2 spike glycoprotein in regulating host signaling pathway

Abstract

Since the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, global public health and the economy have suffered unprecedented damage. Based on the increasing related literature, the characteristics and pathogenic mechanisms of the virus, and epidemiological and clinical features of the disease are being rapidly discovered. The spike glycoprotein (S protein), as a key antigen of SARS-CoV-2 for developing vaccines, antibodies, and drug targets, has been shown to play an important role in viral entry, tissue tropism, and pathogenesis. In this review, we summarize the molecular mechanisms of interaction between S protein and host factors, especially receptor-mediated viral modulation of host signaling pathways, and highlight the progression of potential therapeutic targets, prophylactic and therapeutic agents for prevention and treatment of SARS-CoV-2 infection.

Keywords: ACE2 receptor; S protein; SARS-CoV-2; signaling pathway.

Figure 1

Evolutionary origin and transmission routes of SARS‐CoV‐2. (A) The evolutionary origin and journey of SARS‐CoV‐2 through different primary and intermediate hosts. Different paths of potential viral transmissions are indicated with yellow arrows. (B) The circular phylogenetic tree illustrates the positions of human coronavirus HKU1 (HCoV‐HKU1), human coronavirus OC43 (HCoV‐OC43), Middle East respiratory syndrome coronavirus (MERS‐CoV), Severe acute respiratory syndrome (SARS)‐associated coronavirus (SARS‐CoV and SARS‐CoV‐2) in different host groups. The complete genome sequences were collected from National Center for Biotechnology Information (NCBI) database and analyzed in The Interactive Tree Of Life (https://itol.embl.de) online software tool. A separate phylogenetic tree of HCoV‐HKU1, HCoV‐OC43, MERS‐CoV, SARS‐CoV, and SARS‐CoV‐2 is shown on the right panel.

Figure 2

Regulation of host cell receptors by SARS‐CoV‐2‐Spike protein. (A) Sequential events of viral‐host cell membrane fusion were diagrammatically represented involving SARS‐CoV‐2 spike protein, ACE2, and TMPRSS2 receptors. (B) The expression patterns of human ACE2 and TMPRSS2 receptors in normal tissues were shown by heatmap. The expression patterns were analyzed by the Open Access FunRich functional enrichment analysis tool (http://www.funrich.org/index.html). (C) Cell and tissue tropism of SARS‐CoV‐2. After successful infection, the virus disseminates in different organ tissues of the human body including the lung, pancreas, liver, brain, intestine, heart, and skin.

Figure 3

Structural overview of SARS‐CoV‐2‐Spike protein. Diagrammatic representation of SARS‐CoV‐2 genome, and spike glycoprotein (S) structures. Illustration of full‐length SARS‐CoV‐2 S‐protein domains (N‐terminal, receptor binding domain, C‐terminal), furin cleavage site, fusion peptide, and Heptad repeat regions (HR1 and HR2) are highlighted.

Figure 4

The SARS‐CoV‐2‐Spike protein mediates signaling transduction pathways. The diagram shows SARS‐CoV‐2‐Spike glycoprotein (S) interacts with several host cell receptor proteins mainly with ACE2 by its RBD region. TMPRSS2 initiates the activation of S protein for viral–host cell membrane fusion and subsequent internalization of viral particles inside the cell. SARS‐CoV‐2‐S and ACE2 interaction elicit NF‐κB signaling to regulate different cellular functions. S protein also shows the interaction with cytokine receptors (TLR‐1, 4, 6), glucose‐regulated protein (GRP78), mineralocorticoid receptor (MR), and important growth factor receptor‐neuropilin‐1 (NRP1). Apart from these, SARS‐CoV‐2‐Spike glycoprotein was shown to interact with dendritic cell‐specific intercellular adhesion molecule‐3‐grabbing non‐integrin (DC‐SIGN) for regulating different immunological functions in the host cell.