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FLASH GENE

Symbol

TNFRSF18

contributors: mct - updated : 11-05-2018

HGNC name	tumor necrosis factor receptor superfamily, member 18
HGNC id	11914

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	3.20 kb     5 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004195 5 - 1214 NP_004186 - 241 - 2013 23892569 Cell membrane; single-pass type I membrane protein NM_148901 4 - 1003 NP_683699 - 255 - 2013 23892569 secreted protein NM_148902 5 - 1193 NP_683700 - 234 - 2013 23892569

EXPRESSION

Type	restricted

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 Digestive esophagus           stomach         Lymphoid/Immune lymph node         Respiratory respiratory tract trachea

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Lymphoid/Immune T cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	extracellular N terminus
	three extracytoplasmic cysteine-rich pseudorepeats typical for the TNFR superfamily (3 TNFR-Cys repeats)
	with a preligand assembly domain (PLAD) in CRD1 mediating ligand-independent receptor assembly and signaling,
	a small cytoplasmic tail
	a DEATH domain
	cytoplasmic C terminus, and it shares significant homology in the C-terminal domain with other members of the TNF receptor family

mono polymer

homomer , trimer

HOMOLOGY

Homologene

FAMILY

tumor necrosis factor receptor superfamily

CATEGORY

receptor

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
text	type 1 membrane protein

basic FUNCTION	involved in regulation of T cell receptor-mediated cell death
	may be involved in interactions between activated
	T-lymphocytes and endothelial cells and in the regulation of T-cell receptor-mediated cell death
	TNFRSF18, but also TNFSF18 is capable of transducing signals, and the consequences of TNFRSF18-TNFSF18 interaction may vary among different effector cell types, differ upon signal transduction via the receptor, the ligand, or both, depend on the level of an ongoing immune response
	stimulation of TNFRSF18 on effector CD8 T cells results in high-avidity T cell responses to tumor-specific Ags, thereby inducing potent antitumor immunity in the absence of autoimmunity
	dexamethasone-inducible molecule in T cells
	ligation of TNFRSF18 had profound effects on kinase phosphorylation, surface receptor expression, suppressive activity, and cytokine production
	TNFRSF18 is a coactivating receptor that is constitutively expressed on Treg cells and induced on activated T cells
	contributes to TNFRSF9 expression on CD8 T cells upon their entry into the bone marrow (BM) or liver
	TNFRSF4, TNFRSF18 play important roles in regulating activities of effector and regulatory T cells (Treg)
	expressed on macrophages, drives cytokine release and T cell activation, resulting in neuropathic pain via TNFRSF18-dependent actions
	is likely a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs)
	TNFRSF18 co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

	TNFRSF18 pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability
	involvement of the TNFRSF18/TNFSF18 pathway in interactions with Epidermal keratinocytes (KCs) and Langerhans cells (LCs) and the migration of dendritic cells (DCs)

a component

INTERACTION

DNA

RNA

small molecule

protein	binds to TRAF1, TRAF2, and TRAF3, but not TRAF5 and TRAF6
	receptor for TNFSF18
	TRAF5 plays a crucial role in TNFRSF18-induced signaling pathways that augment T cell activation
	TNFSF18 utilizes multiple oligomerization states to regulate TNFRSF18-mediated signaling during T cell costimulation
	TNFRSF18/TNFSF18 system participates in the development of autoimmune/inflammatory responses and graft vs. host disease and potentiates response to infection and tumors
	stimulation of nTregs through TNFRSF18 initiates a signaling cascade that involves MAP2K7, MAPK8 phosphorylation, JUN activation, and the activation of NFKB1
	platelet-derived TNFSF18 mediates NK-inhibitory forward signaling via TNFRSF18
	enhanced TNFRSF18/TNFSF18 interactions have a pleiotropic role on the regulation of T-cell responses, which includes promoting the differentiation of Tr-1-like cells, which contribute to the maintenance of peripheral T-cell tolerance
	both DNMT1 and methyl-CpG-binding domain Protein 4 (MBD4) bind to the TNFRSF18

cell & other

REGULATION

Other

expression in the TNFRSF18 locus is regulated by NFKB1 and FOXP3 through an enhancer

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in peripherical mononuclear cells after antigen stimulation/lymphocyteactivation

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	should be considered as a marker for isolating Tregs
Therapy target
	System Type Disorder Pubmed miscelleaneous pain   TNFRSF18-TNFSF18 pathway might represent a novel target for the treatment of neuropathic pain

ANIMAL & CELL MODELS

mice lacking the glucocorticoid-induced tumor necrosis factor receptor related protein (Gitr) exhibit defective CD8 T cell accumulation, increased T cell exhaustion and impaired viral control