Unearthing the role of septins in viral infections

Abstract

Septin proteins are a subfamily of closely related GTP-binding proteins conserved in all species except for higher plants and perform essential biological processes. Septins self-assemble into heptameric or octameric complexes and form higher-order structures such as filaments, rings, or gauzes by end-to-end binding. Their close association with cell membrane components makes them central in regulating critical cellular processes. Due to their organisation and properties, septins function as diffusion barriers and are integral in providing scaffolding to support the membrane's curvature and stability of its components. Septins are also involved in vesicle transport and exocytosis through the plasma membrane by co-localising with exocyst protein complexes. Recently, there have been emerging reports of several human and animal diseases linked to septins and abnormalities in their functions. Most of our understanding of the significance of septins during microbial diseases mainly pertains to their roles in bacterial infections but not viruses. This present review focuses on the known roles of septins in host-viral interactions as detailed by various studies.

Keywords: diseases; host-viral interaction; roles; septin.

Figure 1. Schematic diagrams of typical septin sequence with its classification and GTPase activity

Highly conserved GTP-binding domains consist of G1, G3, and G4 motifs, polybasic region, and septin unique elements (SUE) are present in mammalian septins. All septins have various lengths and amino acid sequences of the N-terminal (amino-terminal) and C-terminal (carboxy-terminal). Commonly, septins are classified into four distinct groups: SEPT2 (SEPT1, SEPT2, SEPT4, SEPT5), SEPT3 (SEPT3, SEPT9, SEPT12), SEPT6 (SEPT6, SEPT8, SEPT10, SEPT11, SEPT14), and SEPT7. Almost all septins possessed a slow intrinsic GTPase activity except for the SEPT6 group. This is due to the absence of Thr78 residue that prevents hydrolysis of GTP to GDP in the SEPT6 group.

Figure 2. Cytoskeleton dynamics of septins

GTP-binding domain interface and the carboxy-terminal NC interface of septin subunits interact creating complexes that link end-to-end to form filaments. Septin from several groups are shown in various colours. In humans, it has been demonstrated that septins form complexes with two, three, and/or four septin subunits (canonical and non-canonical complexes). Septin oligomers will undergo polymerization to form a high-order filamentous structure. Later, septin hetero-oligomers establish non-polar filaments that can link up and generate linear bundles filaments and circular ring-like structures.

Figure 3. Septin interactions in viral pathogenesis described in this review

This review focuses on eight pathogenic viruses that are associated with septin functions during pathogenesis in humans (Vaccinia Virus, VACV; Hepatitis C Virus, HCV; Human Herpesvirus, HHV; Zika Virus, ZIKV; Human Immunodeficiency Virus, HIV), aquatic animals (Nodavirus), and poultry animals (Marek's Disease Virus, MDV; Influenza Virus).

Figure 4. Overview of the role of septins in viral infections

SEPT1, SEPT2, SEPT4, SEPT5, SEPT6, SEPT7, SEPT8, SEPT9, and SEPT11 possess antiviral and/or proviral potential depending on the type of viral infections. However, there is a lack of information on the viral interaction of SEPT3, SEPT10, SEPT12, and SEPT14.