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FLASH GENE

Symbol

TLR3

contributors: mct - updated : 18-05-2017

HGNC name	toll-like receptor 3
HGNC id	11849

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	TLR3D toll-like receptor 3 deficiency
Location	4q35.1      Physical location : 186.990.308 - 187.006.250
Synonym name	Drosophila transmembrane receptor Toll homolog 3
	CD283 antigen
Synonym symbol(s)	CD283, IIAE2

DNA

TYPE	functioning gene
STRUCTURE	15.94 kb     5 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	with two alternatively spliced variants (PMID: 9435236) using alternative polyadenylation sites to generate different length transcripts

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003265 5 - 3057 NP_003256 - 904 - 2001 11607032

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine adrenal gland       moderately   pancreas         Lymphoid/Immune spleen       moderately Reproductive female system ovary     highly Homo sapiens Respiratory respiratory tract         Homo sapiens Fetal Skin/Tegument skin         Homo sapiens Fetal Urinary bladder       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Muscular smooth       Homo sapiens Fetal

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune dendritic cell Nervous astrocyte Homo sapiens Reproductive epithelial cell Homo sapiens

cell lineage
cell lines	in benign conditions, epithelial tumors, and in ovarian cancer cell lines
fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	an extracellular part composed of 24 leucine-rich repeats (LRR)
	N-terminal extracellular domain (ECD), located in the interior of endosomes, where it encounters and binds dsRNA and transduces signals that initiate inflammatory and adaptive antiviral responses (
	a cysteine rich region
	a transmembrane segment
	a cytoplasmic domain
	the TolN homology domain (TH), common to the Toll and IL1 receptor genes (also called TIR domain)

conjugated

GlycoP

HOMOLOGY

interspecies	homolog to rattus Tlr3 (80.8 pc)
	homolog to murine Tlr3 (79.9 pc)

Homologene

FAMILY

Toll-like receptor family

CATEGORY

immunity/defense , receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
text	single-pass type I membrane protein
	on the cell surface of fibroblasts, and expressed on the cell surface of epithelial origin
	centrosomal in the dendritic cells
	localized in the endosomal membrane
	endosomal TLR that mediates immune responses against viral infections upon activation by its ligand double-stranded RNA, a replication intermediate of most viruses
	endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved
	localized in the cellular compartments but also at the plasma membrane

basic FUNCTION	involved in pathogen recognition and activation of innate immunity to microbial agents
	acting on the cell surface to sense viral infection
	involved in the recognition of ds-RNA
	immune-recognition receptor that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses
	acting via MyD88 and TRAF6 to lead to NF-kappa-B activation, cytokine secretion and the inflammatory response
	inducing TNF and IL12
	activating cytokines according to pathogen-associated molecular patterns
	activating IRF3 which mediates a specific gene program responsible for innate antiviral responses
	involved in the activation of NF-kappaB-inducing kinase
	can play a nonredundant role in host defense in the setting of a natural ecosystem
	recruits the Toll-interleukin 1 receptor domain (TIR)-containing adapter molecule 1 (TICAM-1) adapter and induces IRF3 activation followed by IFN-beta promoter activation
	highly functional in the esophageal epithelium and TLR3-mediated NF-kappaB signaling may play an important regulatory role in esophageal epithelial homeostasis
	plays complex roles in modulating CNS plasticity
	roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention
	constitutive physiological TLR3 signaling suppresses ERK and CREB activities, suggesting a mechanism whereby TLR3 regulates hippocampal neurogenesis and behavioral plasticity
	engages the adaptor molecule TRIF in order to activate the production of type I interferons
	induces signaling mechanisms involving TICAM1, MAPK14 and MAPKAPK2 to enhance stabilization of IFNB mRNA contributing to enhanced IFNB levels during pathogen infections)
	TLR3 proteolytic processing is essential for its function, suggesting a mechanism of tight control of TLR3 signaling and thus immunity
	serve as a surrogate sensor of retrovirus in human cells
	astrocytic TLR3 plays an important role not only in antiviral response but also in regeneration/healing of the CNS
	key effector of the innate immune system against viruses
	plays an important role in myocardial injury induced by myocardial infarction (MI) or ischemia/reperfusion (I/R)
	endosomal TLR3 senses RNAs derived from cells with viral infection or sterile tissue damage, leading to the induction of type I interferon and cytokine production, as well as dendritic cell maturation
	is a dsRNA sensing receptor that is localized in the cellular compartments but also at the plasma membrane
	TLR3 receptor and ligand endocytosis as well as endosomal acidification are important for the robust signaling of TLR3
	recognition of endogenous RNA by TLR3 is an important step in the program of skin barrier repair
	receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression
	is a key control system in metabolic regulation

CELLULAR PROCESS	cell life, differentiation
	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

immunity/defense

text	apoptosis of infected cells; inhibiting osteoclast differentiation during microbial infection

PATHWAY

metabolism

signaling

signal transduction

a component	dimerization of TLR3 is essential for ligand binding (

INTERACTION

DNA

RNA	binding to double strand RNA

small molecule

protein	binding to MyD88 via their respective TIR domains
	interacting with RFTN1 (Raftlin participates in double-stranded RNA analog, poly(I:C)-induced TLR3 activation)
	STAT3) signaling is an essential mediator of TLR3-regulated protection of RPE cells
	TLR3 and DDX58 activation leads to a release of proinflammatory cytokines, which enhance atherosclerotic processes and affect other cell types
	UNC93B1 is required for processing by transporting TLR3 through the Golgi complex and to the endosomes
	TRIM56 is a positive regulator of TLR3 signaling
	TRIM38 negatively regulates TLR3-mediated type I interferon signaling by targeting TIR domain-containing adaptor inducing IFNB (TICAM1)
	is an important regulator of UNC93B1 that in turn governs the responsiveness of all nucleic acid-sensing (NAS) Toll-like receptors (TLRs)
	TICAM1 is an adapter protein required for TLR3-mediated signaling
	WWP2 mediated K48-linked ubiquitination and degradation of TICAM1 upon TLR3 activation
	RHBDD3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in liver and disrupting NK cell-Kupffer cell interaction
	by inhibiting the degradation of TRAF3 during TLR4 activation, USP25 enables a balanced innate immune response
	TLR3 stimulation in keratinocytes induces a CASP4 dependent release of pro-IL1B, but further processing to active IL1B is limited
	drives CASP8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling
	activation of TLR2 in the skin by commensal microbial products prevents excessive inflammation by blocking downstream TLR3 signaling
	WDFY1 is a crucial adaptor protein in the TLR3/4 signaling pathway
	WDFY1 recruits the signaling adaptor TICAM1 to TLR3 and TLR4, thereby potentiating signaling from these pattern recognition receptors (PRRs)
	S100A9 protein is a critical regulator of TLR3 trafficking
	TRIM38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms
	endosomal localization of endogenous TLR3 was decreased by silencing of LRRC59, suggesting that LRRC59 promotes UNC93B1-mediated translocation of nucleic acid (NA)-sensing TLRs from the ER upon infection
	important distinction between the TICAM1-mediated signaling pathways of TLR4 and TLR3
	ELAVL1 stabilizes ATP6V0D2 mRNA, which is required for the TLR3-mediated innate immune responses

cell & other

REGULATION

activated by

ECM29 depletion that increases Toll-like receptor 3 signaling

Other	regulated by TP53 (TP53 influences TLR3 expression and function and highlight a role of TP53 in innate immune response in epithelial cells)
	TLR3 activation in the skin induces inflammation and increases the expression of genes involved in skin barrier repair

ASSOCIATED DISORDERS

corresponding disease(s)

TLR3D

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       gain of function induces the activation of NF-kappaB and the production of type I interferons (IFNs) constitutional       gain of function can affect the differentiation to myofibroblasts and enhance ECM production via the NF-kappaB-TGF-beta1-dependent pathway constitutional       loss of function may be closely involved in idiopathic nephrotic syndrome (INS) pathogenesis (pMID: 26123900) constitutional       gain of function expression of mRNA for TLR7 was up-regulated in pulmonary alveolar macrophages (AMs) during Respiratory syncytial virus (RSV) infection

Susceptibility

to Herpes Simplex Encephalitis to age-related macular degeneration to End-stage renal disease (ESRD)

Variant & Polymorphism other	mutations associated with childhood herpes simplex encephalitis
	TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells, in age-related macular degeneration
	presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular atheroma   modulation of TLR3 may be an effective approach for ameliorating heart injury in heart attack patients.

ANIMAL & CELL MODELS

	mice exhibit reduced anxiety-like behaviors
	Tlr3-deficient mice responded to experimental challenge with 16 different viruses in various ways