TLR4 (toll like receptor 4)

Gene

• Entrez ID: 7099
• Gene name: Toll like receptor 4
• Gene symbol: TLR4
• Synonyms: ARMD10, CD284, TLR-4, TOLL
• Chromosome: 9
• Chromosome location: 9q33.1
• Summary: The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT003050	hsa-let-7i-5p	Luciferase reporter assay, qRT-PCR, Western blot	17660297
MIRT006530	hsa-miR-146a-5p	ELISA, Luciferase reporter assay, Microarray, qRT-PCR, Western blot	21329689
MIRT018411	hsa-miR-335-5p	Microarray	18185580
MIRT023907	hsa-miR-1-3p	Microarray	18668037
MIRT031004	hsa-miR-21-5p	Microarray	18591254
MIRT053375	hsa-miR-146b-5p	Luciferase reporter assay, qRT-PCR	23798430
MIRT438116	hsa-let-7b-5p	Luciferase reporter assay	23437218
MIRT449826	hsa-miR-526b-5p	PAR-CLIP	22100165
MIRT449827	hsa-miR-6077	PAR-CLIP	22100165
MIRT449828	hsa-miR-7-5p	PAR-CLIP	22100165
MIRT449829	hsa-miR-1468-3p	PAR-CLIP	22100165
MIRT449830	hsa-miR-4698	PAR-CLIP	22100165
MIRT449831	hsa-miR-4694-3p	PAR-CLIP	22100165
MIRT722918	hsa-miR-4659b-3p	HITS-CLIP	19536157
MIRT722919	hsa-miR-4659a-3p	HITS-CLIP	19536157
MIRT722920	hsa-miR-3658	HITS-CLIP	19536157
MIRT722921	hsa-miR-4279	HITS-CLIP	19536157
MIRT722922	hsa-miR-630	HITS-CLIP	19536157
MIRT722923	hsa-miR-4738-3p	HITS-CLIP	19536157
MIRT722924	hsa-miR-942-5p	HITS-CLIP	19536157
MIRT722925	hsa-miR-4742-3p	HITS-CLIP	19536157
MIRT722926	hsa-miR-548g-3p	HITS-CLIP	19536157
MIRT732201	hsa-miR-26b-5p	qRT-PCR, Luciferase reporter assay	26222045
MIRT733014	hsa-miR-181b-2-3p	Luciferase reporter assay, qRT-PCR, Western blot	27641447

Transcription factors

Transcription factor	Regulation	Reference
IRF3	Unknown	22208359
IRF8	Unknown	10734131
SPI1	Activation	16785240;20956019
SPI1	Unknown	10734131
STAT6	Repression	16433852
ZNF160	Repression	19846881

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000187	Process	Activation of MAPK activity	ISS
GO:0001530	Function	Lipopolysaccharide binding	IBA	21873635
GO:0001530	Function	Lipopolysaccharide binding	IMP	16514062
GO:0001530	Function	Lipopolysaccharide binding	NAS	10835634
GO:0001540	Function	Amyloid-beta binding	IC	20037584
GO:0001726	Component	Ruffle	IEA
GO:0001875	Function	Lipopolysaccharide immune receptor activity	IBA	21873635
GO:0001875	Function	Lipopolysaccharide immune receptor activity	IDA	19252480
GO:0001891	Component	Phagocytic cup	IDA	30883606
GO:0002218	Process	Activation of innate immune response	IEA
GO:0002224	Process	Toll-like receptor signaling pathway	IBA	21873635
GO:0002224	Process	Toll-like receptor signaling pathway	TAS
GO:0002322	Process	B cell proliferation involved in immune response	IEA
GO:0002537	Process	Nitric oxide production involved in inflammatory response	IEA
GO:0002730	Process	Regulation of dendritic cell cytokine production	IEA
GO:0002755	Process	MyD88-dependent toll-like receptor signaling pathway	ISS
GO:0002755	Process	MyD88-dependent toll-like receptor signaling pathway	TAS
GO:0002756	Process	MyD88-independent toll-like receptor signaling pathway	TAS
GO:0004888	Function	Transmembrane signaling receptor activity	NAS	11970998
GO:0005102	Function	Signaling receptor binding	IPI	20037584
GO:0005515	Function	Protein binding	IPI	11441107, 11544529, 12925853, 15356101, 15728506, 16622205, 17064675, 17126326, 17258210, 17803912, 19252480, 19509286, 20037584, 20067962, 20547845, 21829704, 21903422, 25187624, 29150600
GO:0005737	Component	Cytoplasm	IDA	19740627
GO:0005737	Component	Cytoplasm	IPI	20037584
GO:0005769	Component	Early endosome	IEA
GO:0005794	Component	Golgi apparatus	IDA
GO:0005886	Component	Plasma membrane	IDA	16338228, 19740627
GO:0005886	Component	Plasma membrane	ISS
GO:0005886	Component	Plasma membrane	TAS
GO:0005887	Component	Integral component of plasma membrane	IBA	21873635
GO:0005887	Component	Integral component of plasma membrane	IDA	15027902
GO:0006909	Process	Phagocytosis	IDA	30883606
GO:0006954	Process	Inflammatory response	IBA	21873635
GO:0006955	Process	Immune response	TAS	10426995
GO:0007249	Process	I-kappaB kinase/NF-kappaB signaling	TAS
GO:0007252	Process	I-kappaB phosphorylation	IDA	19740627
GO:0009897	Component	External side of plasma membrane	IDA	16514062
GO:0009986	Component	Cell surface	IDA	25204797
GO:0010008	Component	Endosome membrane	TAS
GO:0010572	Process	Positive regulation of platelet activation	ISS	16514062
GO:0010628	Process	Positive regulation of gene expression	IMP	23817958
GO:0010628	Process	Positive regulation of gene expression	ISS
GO:0010838	Process	Positive regulation of keratinocyte proliferation	IDA
GO:0014002	Process	Astrocyte development	IEA
GO:0016046	Process	Detection of fungus	NAS	11254600
GO:0030890	Process	Positive regulation of B cell proliferation	IEA
GO:0031226	Component	Intrinsic component of plasma membrane	IDA	11274165
GO:0031663	Process	Lipopolysaccharide-mediated signaling pathway	IDA	10880523
GO:0031663	Process	Lipopolysaccharide-mediated signaling pathway	IGI	10880523
GO:0032496	Process	Response to lipopolysaccharide	IC	16514062
GO:0032496	Process	Response to lipopolysaccharide	IDA	12594207
GO:0032497	Process	Detection of lipopolysaccharide	IDA	19252480
GO:0032611	Process	Interleukin-1 beta production	ISS
GO:0032689	Process	Negative regulation of interferon-gamma production	ISS
GO:0032700	Process	Negative regulation of interleukin-17 production	ISS
GO:0032707	Process	Negative regulation of interleukin-23 production	ISS
GO:0032715	Process	Negative regulation of interleukin-6 production	ISS
GO:0032720	Process	Negative regulation of tumor necrosis factor production	ISS
GO:0032722	Process	Positive regulation of chemokine production	IDA	19740627
GO:0032727	Process	Positive regulation of interferon-alpha production	ISS
GO:0032728	Process	Positive regulation of interferon-beta production	ISS
GO:0032729	Process	Positive regulation of interferon-gamma production	ISS
GO:0032731	Process	Positive regulation of interleukin-1 beta production	IDA	11432859
GO:0032732	Process	Positive regulation of interleukin-1 production	ISS
GO:0032733	Process	Positive regulation of interleukin-10 production	ISS
GO:0032735	Process	Positive regulation of interleukin-12 production	IDA	15027902
GO:0032735	Process	Positive regulation of interleukin-12 production	ISS
GO:0032755	Process	Positive regulation of interleukin-6 production	IDA	19740627
GO:0032755	Process	Positive regulation of interleukin-6 production	IMP	21329689, 30321456
GO:0032757	Process	Positive regulation of interleukin-8 production	IDA	17951129, 19740627, 21329689
GO:0032760	Process	Positive regulation of tumor necrosis factor production	IDA	17951129
GO:0032760	Process	Positive regulation of tumor necrosis factor production	IMP	30321456
GO:0032760	Process	Positive regulation of tumor necrosis factor production	ISS
GO:0034128	Process	Negative regulation of MyD88-independent toll-like receptor signaling pathway	TAS
GO:0034142	Process	Toll-like receptor 4 signaling pathway	TAS
GO:0035666	Process	TRIF-dependent toll-like receptor signaling pathway	ISS
GO:0035666	Process	TRIF-dependent toll-like receptor signaling pathway	TAS
GO:0038023	Function	Signaling receptor activity	IBA	21873635
GO:0042088	Process	T-helper 1 type immune response	NAS	11970998
GO:0042116	Process	Macrophage activation	IMP	10835634
GO:0042742	Process	Defense response to bacterium	IGI	30321456
GO:0042742	Process	Defense response to bacterium	TAS	10426995
GO:0042802	Function	Identical protein binding	IPI	23059983, 23155421
GO:0043032	Process	Positive regulation of macrophage activation	ISS
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IEA
GO:0043235	Component	Receptor complex	IPI	20037584
GO:0045087	Process	Innate immune response	TAS	15356140
GO:0045348	Process	Positive regulation of MHC class II biosynthetic process	IEA
GO:0045429	Process	Positive regulation of nitric oxide biosynthetic process	ISS
GO:0045671	Process	Negative regulation of osteoclast differentiation	NAS	12133979
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	ISS
GO:0046330	Process	Positive regulation of JNK cascade	IEA
GO:0046696	Component	Lipopolysaccharide receptor complex	IDA	11274165, 19252480
GO:0046982	Function	Protein heterodimerization activity	IPI	20037584
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	15027902
GO:0050135	Function	NAD(P)+ nucleosidase activity	IEA
GO:0050729	Process	Positive regulation of inflammatory response	IC	19740627
GO:0050729	Process	Positive regulation of inflammatory response	IMP	21329689
GO:0050829	Process	Defense response to Gram-negative bacterium	IBA	21873635
GO:0050829	Process	Defense response to Gram-negative bacterium	IC	16514062
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IDA	12594207, 29038465
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IGI	20037584
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IMP	30233718
GO:0051770	Process	Positive regulation of nitric-oxide synthase biosynthetic process	ISS
GO:0060729	Process	Intestinal epithelial structure maintenance	ISS
GO:0060907	Process	Positive regulation of macrophage cytokine production	IEA
GO:0061809	Function	NAD+ nucleotidase, cyclic ADP-ribose generating	IEA
GO:0070266	Process	Necroptotic process	TAS
GO:0070373	Process	Negative regulation of ERK1 and ERK2 cascade	ISS
GO:0070374	Process	Positive regulation of ERK1 and ERK2 cascade	IEA
GO:0070430	Process	Positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway	IEA
GO:0070434	Process	Positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	IEA
GO:0071222	Process	Cellular response to lipopolysaccharide	IDA	11432859
GO:0071222	Process	Cellular response to lipopolysaccharide	IGI	30321456
GO:0071222	Process	Cellular response to lipopolysaccharide	ISS
GO:0071223	Process	Cellular response to lipoteichoic acid	IEA
GO:0071260	Process	Cellular response to mechanical stimulus	IEP	19593445
GO:0071346	Process	Cellular response to interferon-gamma	IDA	11672593
GO:0097190	Process	Apoptotic signaling pathway	TAS
GO:0120163	Process	Negative regulation of cold-induced thermogenesis	ISS	26370079
GO:0140052	Process	Cellular response to oxidised low-density lipoprotein particle stimulus	ISS
GO:1900017	Process	Positive regulation of cytokine production involved in inflammatory response	IMP	30321456
GO:1900017	Process	Positive regulation of cytokine production involved in inflammatory response	ISS
GO:1900227	Process	Positive regulation of NLRP3 inflammasome complex assembly	ISS
GO:1901224	Process	Positive regulation of NIK/NF-kappaB signaling	IDA	19740627
GO:1903223	Process	Positive regulation of oxidative stress-induced neuron death	ISS
GO:1903428	Process	Positive regulation of reactive oxygen species biosynthetic process	ISS
GO:1903974	Process	Positive regulation of cellular response to macrophage colony-stimulating factor stimulus	IDA	11672593
GO:1904466	Process	Positive regulation of matrix metallopeptidase secretion	IMP	21329689
GO:1904646	Process	Cellular response to amyloid-beta	IGI	20037584
GO:2000343	Process	Positive regulation of chemokine (C-X-C motif) ligand 2 production	IMP	21329689

Other IDs

• MIM: 603030
• HGNC: 11850
• e!Ensembl: ENSG00000136869

Protein

• UniProt ID: O00206
• Protein name: Toll-like receptor 4 (EC 3.2.2.6) (hToll) (CD antigen CD284)
• Protein function: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195,PubMed:21393102). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759). Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465).
• PDB: 2Z62, 2Z63, 2Z65, 2Z66, 3FXI, 3UL7, 3UL8, 3UL9, 3ULA, 4G8A, 5NAM, 5NAO
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF13855	LRR_8	55 → 114	Leucine rich repeat	Repeat
  PF13855	LRR_8	78 → 138	Leucine rich repeat	Repeat
  PF13855	LRR_8	126 → 187	Leucine rich repeat	Repeat
  PF13855	LRR_8	150 → 207	Leucine rich repeat	Repeat
  PF13855	LRR_8	447 → 508	Leucine rich repeat	Repeat
  PF13855	LRR_8	485 → 532	Leucine rich repeat	Repeat
  PF13855	LRR_8	496 → 556	Leucine rich repeat	Repeat
  PF01582	TIR	674 → 839	TIR domain	Family

• Sequence:

  MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLD
  LSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALG
  AFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHL
  DLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSL
  NVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDI
  IDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTS
  NKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLG
  LEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAG
  NSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPY
  KCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQL
  LVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLML
  LAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAA
  NIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLR
  QQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI

• Sequence length: 839