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Table 5 Functional annotation of candidate genes/proteins from the ECM proteoglycans - cell periphery set, interacting with genes/proteins from the TBEVHostDB and loaded with harmful variants most heavily (N > 3)

From: Exome-wide search and functional annotation of genes associated in patients with severe tick-borne encephalitis in a Russian population

No Gene N a Number of neighborsb Functional annotation
1. MSR1 5 1 MSR1 gene encodes macrophage scavenger receptor 1. Macrophage scavenger receptors mediate the endocytosis of a diverse group of macromolecules. Expression of MSR1 promotes alternative activation of murine macrophages following hepatic viral infection [126]. On the other hand, it is known, that Flaviviruses enter host cells through the process of clathrin-mediated endocytosis [127, 128]. Thus, MSR1 may interfere with this process.
2. LMO7 5 1 LMO7 gene encodes LIM domain only protein 7 with three conserved domains: (1) the CH (Calponin Homology) domain, known to confer the actin-binding ability on many actin-associated proteins; (2) the PDZ domain, a region containing a conserved Gly-Leu-Gly-Phe repeat sequence, may take part in protein targeting and protein complex assembly; (3) LIM (Lin-11-Isl-1-Mec-3) domain, that may regulate transcription or cytoskeleton assembly [129]. Thus LMO7 is known to be a nucleocytoplasmic shuttling protein that possesses both actin-binding and transcription regulator activities [130]. There are no evidence confirming involvement of LMO7 in response to viral infection, nevertheless we propose that it may play a role in host response, due to its involvement in cytoskeletal reorganization and transcription regulation processes.
3. FLNA 4 7 FLNA gene encodes filamin A (also known as ABP-280). Filamin A is ubiquitous dimeric actin cross-linking phosphoprotein, located in peripheral cytoplasm, where it promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins [131].
4. PALLD 4 1 PALLD gene encodes palladin, actin-associated protein. Palladin is a cytoskeletal scaffold protein that may promote tumor cell invasion by linking extracellular matrix degradation in actin-based pseudopods to cell cytoskeleton [132].
5. PKD1 4 1 PKD1 (polycystic kidney disease 1) gene encodes polycystin 1, a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. Polycystin 1 is an integral membrane protein, associated with the cytoskeleton [133] and involved in cell-cell/matrix interactions [134]. Polycystin 1 regulates actin cytoskeleton rearrangements and directional cell migration [135].
6. COBL 3 1 COBL gene encodes cordon-bleu WH2 repeat protein working as a dynamizer of actin assembly [136].
7. FLNC 3 2 FLNC gene encodes filamin C that is one of three related filamin proteins involved in remodeling of the actin cytoskeleton. Filamin C is a predominantly expressed filamin isoform in striated muscles [137].
8. RTN4 3 2 RTN4 gene encodes reticulon 4 (also known as NOGO), an important axonal growth inhibitor in the adult and developing central nervous system. Reticulon 4 may act as a molecular linker between microtubules and actin cytoskeleton in rat vascular smooth muscle cells [138]. RTN4 has been shown to inhibit migration and cell spreading of neuronal and nonneuronal cell types [139].
9. NOD2 3 2 NOD2 gene can function as a cytoplasmic viral pattern-recognition receptor by recognizing viral ssRNA genome and then by triggering activation of interferon-regulatory factor 3 (IRF3) and production of interferon-beta [140].
10. CXCR1 3 1 CXCR1 gene encodes C-X-C motif chemokine receptor 1 (also known as a receptor for interleukin 8). It was found that infection with dengue virus induces interleukin 8 secretion, which increases endothelial cell permeability; this has been proposed as a mechanism for plasma leakage in dengue hemorrhagic fever [141]. It was also found that while infection with West Nile virus the production of interleukin 8 was induced too [142].
11. PIK3CD 3 1 PIK3CD gene encodes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta. Phosphoinositide 3-kinases phosphorylate inositol lipids and are involved in the immune response. It was found that when human Caco-2 cells were pre-treated with inhibitor of PI3K pathway, TBEV cell entry was efficiently blocked [101]
12. VCAN 3 5 VCAN gene encodes versican core protein. This is a large chondroitin sulfate proteoglycan and is a major component of the extracellular matrix. This protein is involved in cell adhesion, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance [143]. Versican is known as an interferon-stimulated gene contributing to fine control of innate immunity [144]. In a mouse model it was shown that versican could mediate inflammatory response to viral infection and could generate an extracellular matrix that promoted leukocyte infiltration and adhesion [145]
13. ANXA7 3 4 ANXA7 gene encodes a membrane binding protein annexin A7 possessing integrin binding activity [146]. As a GTPase, annexin A7 interacts with TIA1 in regulating vascular endothelial cell autophagy [147]. The functional importance of autophagy during TBEV replication was studied in human neuroblastoma cells; stimulation of autophagy resulted in significantly increased dose-dependent TBEV production, whereas the inhibition of autophagy showed a profound, dose-dependent decrease of the yield of infectious virus [148].
14. GSR 3 1 GSR gene encodes glutathione-disulfide reductase, the central enzyme of cellular antioxidant defense. Like other flaviviruses, TBEV may promote oxidative stress in the host cell [74]. As a result, the antioxidant defense system may be significantly perturbed. Thus, it was found that the level of glutathione-disulfide reductase was significantly reduced in the red blood cells isolated from individuals with human immunodeficiency virus infection [149] or, on the contrary, was increased in Huh-7 cell line infected with HCV [150].
15 NEDD4 3 3 NEDD4 (neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase) gene encodes E3 ubiquitin-protein ligase NEDD4. It plays critical role in the regulation of a number of membrane receptors and endocytic machinery. The role of Nedd4-like ubiquitin ligases in virus budding has been established. Nedd4 promotes Japanese encephalitis virus replication by suppressing autophagy [151] and may facilitate HIV-1 release [152].
  1. aN denotes the number of rare harmful minor alleles that were found in exomes of patients with TBE
  2. bThe number of genes/proteins from the TBEVHostDB that had PPIs with the gene/protein in question