Beyond RGD: virus interactions with integrins

Abstract

Viruses successfully infect host cells by initially binding to the surfaces of the cells, followed by an intricate entry process. As multifunctional heterodimeric cell-surface receptor molecules, integrins have been shown to usefully serve as entry receptors for a plethora of viruses. However, the exact role(s) of integrins in viral pathogen internalization has yet to be elaborately described. Notably, several viruses harbor integrin-recognition motifs displayed on viral envelope/capsid-associated proteins. The most common of these motifs is the minimal peptide sequence for binding integrins, RGD (Arg-Gly-Asp), which is known for its role in virus infection via its ability to interact with over half of the more than 20 known integrins. Not all virus-integrin interactions are RGD-dependent, however. Non-RGD-binding integrins have also been shown to effectively promote virus entry and infection as well. Such virus-integrin binding is shown to facilitate adhesion, cytoskeleton rearrangement, integrin activation, and increased intracellular signaling. Also, we have attempted to discuss the role of carbohydrate moieties in virus interactions with receptor-like host cell surface integrins that drive the process of internalization. As much as possible, this article examines the published literature regarding the role of integrins in terms of virus infection and virus-encoded glycosylated proteins that mediate interactions with integrins, and it explores the idea of targeting these receptors as a therapeutic treatment option.

Host receptors: the key to establishing cells with broad viral tropism for vaccine production

“…Integrins are a large family of transmembrane glycoproteins found in a variety of organisms ranging from sponges, corals, nematodes, echinoderms to mammals (Srichai and Zent 2010). These molecules are heterodimeric receptors consisting of different combinations between 18 a and 8 b subunits, which form at least 24 integrins (Hussein et al 2015) (Figure 6(A)). Each integrin subunit consists of three domains, the extracellular, transmembrane and cytoplasmic domains.…”

A potential role for integrins in host cell entry by SARS-CoV-2

“…The RGD motif is the minimal peptide sequence required for binding proteins of the integrin family, which are commonly used as receptors by many human viruses (Hussein et al, 2015). RGD motif integrin-binding is essential for human metapneumovirus (HMPV) (Chang et al, 2012;Wei et al, 2014), human Adenovirus type 2/5 (Wickham et al, 1994), human cytomegalovirus (HHV-5) (Feire et al, 2004), Kaposi's sarcoma-associated virus (HHV-8) (Hussein et al, 2015), Epstein-Barr virus (HHV-4) (Xiao et al, 2008, p. 2), Rotavirus (RV) (Zárate et al, 2004), and Coxsackievirus A9 (Williams et al, 2004). The conservation of the motif and its localization in the receptor-binding region of the SARS-CoV-2 spike protein suggests that integrins may be alternative receptors for this virus.…”

“…Integrins are heterodimeric cell surface receptors that play roles in cell adhesion, cell migration, and cell signaling processes (Hynes, 2002). Viral proteins with RGD motifs promote infection by binding integrin heterodimers such as αVβ1, αVβ3, αVβ5, αVβ6, αVβ8, α5β1, α8β1 and αIIbβ3 (Hussein et al, 2015), activating transducing pathways involving phosphatidylinositol-3 kinase (PI-3K) or mitogen-activate protein kinase (MAPK), which promote virus entry and infection of the host cell. Adenoviruses of serotypes 2 and 5 possess such proteins, Fig.…”

Inclusion of an Arg-Gly-Asp receptor-recognition motif into the capsid protein of rabbit hemorrhagic disease virus enables culture of the virus in vitro

“…The basis of our work is that the integrins of host cells can recognize the RGD peptide that is located at the surface of some microbial pathogens and thereby mediate entry of the pathogens into host cells. The integrin-RGD recognition system plays an important role in various cellular activities, including cell survival, proliferation, determination of morphology, attachment, migration, and angiogenesis (33). In addition, integrins are essential for numerous other important biological events such as embryonic development (17), tumor metastasis (34), wound healing (35), and inflammatory responses (36).…”