Lineage-specific evolution of T-cell immunoglobulin and mucin domain 1 gene in the primates.
ABSTRACT T-cell immunoglobulin domain and mucin domain containing protein 1 (TIM1), also known as a cellular receptor for hepatitis A virus (HAVCR1) or a molecule induced by ischemic injury in the kidney (KIM1), is involved in the regulation of immune responses. We investigated a natural selection history of TIM1 by comparative sequencing analysis in 24 different primates. It was found that TIM1 had become a pseudogene in multiple lineages of the New World monkey. We also investigated T cell lines originated from four different New World monkey species and confirmed that TIM1 was not expressed at the mRNA level. On the other hand, there were ten amino acid sites in the Ig domain of TIM1 in the other primates, which were suggested to be under positive natural selection. In addition, mucin domain of TIM1 was highly polymorphic in the Old World monkeys, which might be under balanced selection. These data suggested that TIM1 underwent a lineage-specific evolutionary pathway in the primates.
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ABSTRACT: The cell surface receptor, T cell immunoglobulin mucin domain-1 (TIM-1), dramatically enhances filovirus infection of epithelial cells. Here, we showed that key phosphatidylserine (PtdSer) binding residues of the TIM-1 IgV domain are critical for Ebola virus (EBOV) entry through direct interaction with PtdSer on the viral envelope. PtdSer liposomes, but not phosphatidylcholine liposomes, competed with TIM-1 for EBOV pseudovirion binding and transduction. Further, Annexin V (AnxV) substituted for the TIM-1 IgV domain, supporting a PtdSer-dependent mechanism. Our findings suggest TIM-1-dependent uptake of EBOV occurs by apoptotic mimicry. Additionally, TIM-1 enhanced infection of a wide range of enveloped viruses, including alphaviruses and a baculovirus. As further evidence of the critical role of enveloped virion associated PtdSer in TIM-1-mediated uptake, TIM-1 enhanced internalization of pseudovirions and VLPs lacking a glycoprotein, providing evidence that TIM-1 and PtdSer-binding receptors can mediate virus uptake independent of a glycoprotein. These results provide evidence for a broad role of TIM-1 as a PtdSer-binding receptor that mediates enveloped virus uptake. Utilization of PtdSer-binding receptors may explain the wide tropism of many of these viruses and provide new avenues for controlling their virulence.Journal of Virology 05/2013; · 5.08 Impact Factor
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ABSTRACT: T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members were recently identified as phosphatidylserine (PtdSer)-mediated virus entry enhancing receptors (PVEERs). These proteins enhance entry of Ebola virus (EBOV) and other viruses by binding PtdSer on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. The PtdSer binding activity of the IgV domain is essential for both virus binding and internalization by TIM-1. However, TIM-3, whose IgV domain also binds PtdSer, does not effectively enhance virus entry indicating that other domains of TIM proteins are functionally important. Here, we investigate the domains supporting enhancement of enveloped virus entry, thereby defining the features necessary for a functional PVEER. Using a variety of chimeras and deletion mutants, we found that in addition to a functional PtdSer binding domain PVEERs require a stalk domain of sufficient length, containing sequences that promote an extended structure. Neither the cytoplasmic nor transmembrane domain of TIM-1 is essential for enhancing virus entry, provided the protein is still plasma membrane bound. Based on these defined characteristics, we generated a mimic lacking TIM sequences and composed of Annexin V, the mucin like domain of α-dystroglycan, and a glycophosphatidylinositol anchor that functioned as a PVEER to enhance transduction of virions displaying Ebola, Chikungunya, Ross River, or Sindbis virus glycoproteins. This identification of the key features necessary for PtdSer-mediated enhancement of virus entry provides a basis for more effective recognition of unknown PVEERs. IMPORTANCE (NONTECHNICAL, 150 WORD LIMIT):: T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members are recently identified phosphatidylserine (PtdSer)-mediated virus entry enhancing receptors (PVEERs). These proteins enhance virus entry by binding the phospholipid, PtdSer, present on the viral membrane. While it is known that the PtdSer binding is essential for the PVEER function of TIM-1, TIM-3 shares this binding activity but does not enhance virus entry. No comprehensive studies have been done to characterize the other domains of TIM-1. In this study, using a variety of chimeric proteins and deletion mutants, we define the features necessary for a functional PVEER. With these features in mind, we generated a TIM-1 mimic using functionally similar domains from other proteins. This mimic, like TIM-1, effectively enhanced transduction. These studies provide insight into the key features necessary for PVEERs and will allow for more effective identification of unknown PVEERs.Journal of Virology 04/2014; · 5.08 Impact Factor
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ABSTRACT: The present study aimed to investigate the expression and association of the single-nucleotide polymorphism (SNP) -1637A/G in the promoter region of the T cell immunoglobulin domain and mucin domain protein-1 (Tim-1) gene in patients diagnosed with thymoma with or without myasthenia gravis (MG). The expression of Tim-1 was detected using the streptavidin peroxidase immunohistochemical staining method on tissues obtained from thymoma patients with (n=58) and without (n=62) MG. The Tim-1 gene -1637A/G polymorphism was detected using the single allele-specific primer polymerase chain reaction. The positive rate of Tim-1 expression in thymoma patients with MG was 62.1% (32/58), which was significantly higher compared with that in thymoma patients without MG (33.9%, 21/62) (P=0.002). The genotype frequencies of GG, GA and AA in the -1637A/G polymorphism were 0.7931, 0.2069 and 0, respectively, in thymoma patients with MG, and 0.6129, 0.3871 and 0, respectively, in thymoma patients without MG. A significant difference in the genotypes between the thymoma patients with MG and those without MG was found (P=0.031). In addition, a significant difference in allele frequencies between thymoma patients with MG and those without MG (P=0.024) was observed. The high expression of Tim-1 in thymoma tissues may play an important role in the development of thymoma with MG. The -1637A/G polymorphism site of the promoter region in Tim-1 may be associated with thymoma with MG. These findings provide a basis for further genetic research of thymoma with MG.Oncology letters 07/2014; 8(1):317-322. · 0.24 Impact Factor