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.
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].
(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.
