UniProtKB/Swiss-Prot Summary for CLDN1 Gene
Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members play essential roles in the formation of impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN1 is required to prevent the paracellular diffusion of small molecules through tight junctions in the epidermis and is required for the normal barrier function of the skin. Required for normal water homeostasis and to prevent excessive water loss through the skin, probably via an indirect effect on the expression levels of other proteins, since CLDN1 itself seems to be dispensable for water barrier formation in keratinocyte tight junctions (PubMed:23407391). ( CLD1_HUMAN,O95832 )
(Microbial infection) Acts as a co-receptor for hepatitis C virus (HCV) in hepatocytes (PubMed:17325668, 20375010, 24038151). Associates with CD81 and the CLDN1-CD81 receptor complex is essential for HCV entry into host cell (PubMed:20375010).
Acts as a receptor for dengue virus (PubMed:24074594). ( CLD1_HUMAN,O95832 ) Dengue disease is becoming a huge public health concern around the world as more than one-third of the world's population living in areas at risk of infection. In an effort to assess host factors interacting with dengue virus, we identified claudin-1, a major tight junction component, as an essential cell surface protein for dengue virus entry. When claudin-1 was knocked down in Huh 7.5 cells via shRNA, the amount of dengue virus entering host cells was reduced. Consequently, the progeny virus productions were decreased and dengue virus-induced CPE was prevented. Furthermore, restoring the expression of claudin-1 in the knockdown cells facilitated dengue virus entry. The interaction between claudin-1 and dengue viral prM protein was further demonstrated using the pull-down assay. Deletion of the extracellular loop 1 (ECL1) of claudin-1 abolished such interaction, so did point mutations C54A, C64A and I32M on ECL1. These results suggest that the interaction between viral protein prM and host protein claudin-1 was essential for dengue entry. Since host and viral factors involved in virus entry are promising therapeutic targets, determining the essential role of claudin-1 could lead to the discovery of entry inhibitors with attractive therapeutic potential against dengue disease.
- AI mainitsee että Dengue käyttää useita reseptoreita. Katson jonki artikkelin.
https://link.springer.com/article/10.1007/s40475-013-0002-7
Glycosaminoglycans (GAGs) and other attachment factors
The first molecule that was identified to participate in DENV entry into mammalian cells was heparan sulfate [20–22]. Highly sulfated GAGs are ubiquitous molecules present on the surface of several types of cells, also mediating attachment for many viruses [23]. It is documented that there are electrostatic attractions among a dengue virus E glycoprotein and the negatively charged carbohydrate moieties present in GAGs [24]. Due to the documented evidence that the GAGs-DENV interactions are stronger when the virus has been passaged in cell-culture repetitively, and due to its correlation with in vivo attenuation, it has been suggested its role is artifactual.
The most relevant attachment factor for DENV entry identified so far is the calcium-dependent lectin, dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) [25–27]. This receptor has high affinity for high-mannose ligands [28]. During the mosquito blood-meal, DENV is deposited in the dermis where its interaction with resident dendritic cells (Langerhans cells) has been documented [6]. Upon entry, dendritic cells migrate to draining lymph nodes where the infection is spread to immune-competent myelo-monocytic cells. Whether DC-SIGN is the only factor responsible for dengue virus entry or the virus replicates actively in dendritic cells is still unknown.
Another lectin that may play a role in dengue virus attachment is the C-type lectin domain family-5 member A (CLEC5) [29, 30]. This molecule has been documented to participate in viral attachment and release of pro-inflammatory mediators important in the pathogenesis of severe forms of dengue [31, 32]. In sum, it is clear that the first step in dengue virus entry involves attachment of the virion to the cell surface.
Cell surface chaperones
Among DENV entry factors identified thus far, there is a group that has been described by independent groups, the surface chaperones. Experimentally, these molecules have been found through binding assays using the envelope glycoprotein as a ligand. HSP-90, HSP-70 and GRP-78 are thought to be part of a receptor complex that mediates dengue entry into human cells from monocytic, neural and hepatic origin [33, 34]. It is not known whether their extracellular function is similar to their well-known intracellular, ATP-dependent protein folding activity, or how they associate with the cell membrane. It has been long been reported that lipopolysaccharide (LPS) inhibits DENV entry into monocytes [35]. This effect is dose dependent. On this regard, surface HSPs were also documented as part of an interacting cluster of plasmatic proteins mediating physiological effects of LPS sensing on cells [36]. It is tempting to propose that heat shock as an effect on DENV entry through the increase of heat-shock-responsive molecules on the surface of infected cells. This effect was documented in the infection of a monocytic cell line [37]. Another protein with chaperone function reported as a DENV receptor is the protein disulfide isomerase (PDI). This has been implicated in DENV entry into endothelial cells [38•]. Besides its important role in the endoplasmic reticulum, it has been detected on the cell surface of lymphocytes [39], platelets [40, 41], and endothelial cells [38•]. PDI has been implicated in entry of several viruses such as polyomavirus [42], New Castle disease virus [43], and the human immunodeficiency virus [39, 44, 45].
Lipid receptors
(PtdSer)rec TIM1-TAM ligands
The only gain-of-function screening in the search for DENV receptors found that phosphatydilserine (PtdSer) receptors TIM-1 (T cell immunoglobulin domain and mucin domain) directly and indirectly through TAM ligands, are relevant on DENV entry into the human 293 T cell line [46•]. These receptors mediate binding of apoptotic cells to be scavenged and immunotolerance. Therefore, an intimate interaction of cell receptors with lipids present on the virion membrane envelope suggests the structure of entering particles needs to be revisited. In any case, the lipid content present on the target cell has long been demonstrated as important to optimize DENV entry.
Inga kommentarer:
Skicka en kommentar