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Table 6 Functional annotation of candidate genes/proteins from the associated_harmful set, interacting with genes/proteins from the TBEVHostDB database

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

No Gene Number of neighborsa Functional annotation
1. WDFY4 b 1 WDFY4 gene encodes WDFY family member 4, which has a predicted BEACH domain and five WD domains at the C-terminal side. WDFY4 may interact with pattern recognition receptors TLR3, TLR4, TLR9 (playing a key role in the innate immune system) and MDA5 (activator of antiviral signaling) and may augment the NF-κB activation by these receptors. WDFY4 is expressed in dendritic cells, neutrophils, B cells and macrophages [99].
2. ALK 3 ALK gene encodes ALK receptor tyrosine kinase, a transmembrane receptor tyrosine kinase from the insulin receptor superfamily. The growth factors pleiotrophin and neurite growth-promoting factor 2 are ligands for ALK and upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. ALK can also drive NF-κB activation, and that activation is increased with the presence of insulin receptor substrate-1 [154]
3. MAP4 b 1 MAP4 gene encodes microtubule associated protein 4. Microtubules are involved in the trafficking of internalized virus from early endosomes to lysosomes for uncoating [95]. MAP4 is one of the human proteins exploited by HIV in order to replicate and bearing strong signatures of positive selection [96]. Knockdown of MAP4 produces post-fusion and pre-nuclear translocation impairment in HIV-1 replication [97].
4. EPPK1 1 EPPK1 gene encodes epiplakin 1. Epiplakin 1 is a member of the plakin family with multiple copies of the plakin repeat domain. Epiplakin is associated with assembled intermediate filaments over keratin monomers and with vimentin intermediate filaments network [155]. Together with the other components of the cytoskeleton, the intermediate filaments have been observed to be involved in flavivirus entry, assembly, and budding processes in the host cells [156]. For example, Zika virus infection causes a drastic reorganization of microtubules and intermediate filaments forming cage-like structures surrounding the viral replication factory [157]
5. BNIPL 1 BNIPL gene encodes BCL2 interacting protein like. It is a member of BNIPL family, which interacts with apoptosis regulators Bcl-2 and Cdc42. BNIPL-2 may be a linker protein located at the front end of Bcl-2 pathway for DNA fragmentation and Cdc42 signaling for morphological changes during apoptosis [158]. Direct killing of the neurons by apoptosis has been reported for such flaviviruses as Langat virus and TBEV in cell culture [159, 160]. Enforced BCL2 expression may attain Japanese encephalitis virus persistence in baby hamster kidney (BHK-21) and Chinese hamster ovary (CHO) cells by restriction of virus-induced cytopathic effects [161]
  1. aThe number of genes/proteins from the TBEVHostDB that had PPIs with the gene/protein in question
  2. bWDFY4 and MAP4 are two of eight genes found in the intersection between the cases-only set and associated_harmful set (Fig. 2)