Identification of Most Lethal Non-synonymous SNPs in Tollip gene- An In-Silico Analysis

Abstract

The Toll-interacting protein (TOLLIP), first detected by hybrid screening using Interleukin-1 receptor accessory protein in 2000, is ubiquitous and its TLR signaling cascade gets negatively regulated by TOLLIP in particular by impeding the TLR4 and TLR2 pathways. Toll-interacting protein facilitates TLR and TGF-β type 1 receptor intracellular localization and lysosomal degradation and exerts its anti-apoptosis and pro-autophagy effects through interaction with a target of Myb1 membrane trafficking protein 1 (TOM1) in autoimmunity. It also protects intestinal epithelial cells from apoptosis induced by (TNF-α) (IFN-γ) signaling and acts as a cargo adaptor linking (ATG8) autophagy gene 8 and microtubule-associated protein 1 light chain 3. Ubiquitin-modified cell debris along with coated autophagosomes removes harmful protein aggregates and maintains cellular homeostasis. It is therefore structurally and functionally important to detect TOLLIP polymorphisms to indicate the possible malfunctions and therapeutics. We have identified the gap of available data on nsSNPs in the TOLLIP gene in previous studies. Hence, We have used a wide range of bioinformatic techniques in this study to identify the most destructive nsSNPs in the TOLLIP gene. The in-silico tools such as PROVEAN, SIFT, SNP&GO, PhD SNP, and PolyPhen2 have been used followed by I Mutant, MutPred, and ConSurf. The 3-D mapping was carried out with I-TASSER and Phyre2. Though, STRING and GeneMANIA proposed the gene to gene interaction of TOLLIP. Our study identified G19D (rs866744102), G32R (rs1308704061), D71N (rs777772934), and E72G (rs1202660177) as the four most lethal non-synonymous SNPs in TOLLIP genes, which may play an essential part in defects of TOLLIP Protein and probably cause a different type of diseases. This is the first study of its kind, and it could pave the way in the field of medical drugs in the future. The influence of these nsSNPs in the normal functioning of TOLLIP can also be evaluated in animal models to identify the underlying biochemical pathway involved in diseases.