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FLASH GENE

Symbol

NOS2

contributors: mct/npt - updated : 10-10-2018

HGNC name	nitric oxide synthase 2, inducible
HGNC id	7873

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	17q11.2      Physical location : 26.083.792 - 26.127.555
Synonym name	nitric oxide synthase 2A (inducible, hepatocytes)
	hepatocyte NOS
	nitric oxide synthase, macrophage
	NOS, type II
	inducible NO synthase
Synonym symbol(s)	NOS, INOS, NOS2A, HEP-NOS
EC.number	1.14.13.39

DNA

TYPE	functioning gene
STRUCTURE	43.76 kb     27 Exon(s)

regulatory sequence	Promoter
	Binding site   enhancer   hormone
text structure	A-activator binding site (AABS) located at -192 nucleotides in the promoter region
	NOS2 gene is highly methylated around the NOS2 transcription start site
	epigenetic regulation of NOS2 by CASP1 involves cleavage of the chromatin regulator PARP1 and chromatin accessibility of the NFKB1 binding sites located at the NOS2 promoter
	octamer (Oct) element in NOS2 proximal promoter, located close to the TATA box, that constitutively binds POU2F1 and its deletion abrogates cytokine-induced transcription

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000625 27 - 4206 NP_000616 131 1153 - 2016 29637536

EXPRESSION

Type

widely

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 intestine       highly   pancreas exocrine       moderately   pharynx       highly   stomach       moderately Lymphoid/Immune           Homo sapiens Nervous brain         Homo sapiens Reproductive female system breast mammary gland   moderately Respiratory lung           respiratory tract trachea     moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic         Connective bone       Connective cartilage       Epithelial barrier/lining       Nervous central

cells

System Cell Pubmed Species Stage Rna symbol   chondrocyte Digestive hepatocyte Lymphoid/Immune activated B lymphocyte Homo sapiens Lymphoid/Immune macrophage Nervous neuron Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a flavodoxin-like domain
	an FAD/NAD(P) binding FR-type domain
	an oxidoreductase domain

mono polymer

homomer , dimer

HOMOLOGY

interspecies	homolog to rattus Nos2 (80.2 pc)
	homolog to murine Nos2 (81.2 pc)

intraspecies	paralog to nitrite oxide synthases
	homolog to sequences found in the SMS repeat gene clusters SMS-REPD,SMS-REPM,REPP (see symbols)

Homologene

FAMILY

NOS family

CATEGORY

enzyme , immunity/defense , transport carrier

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,peroxisome
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus
text	cortical cytoskeletal
	perinuclear region of cytoplasm

basic FUNCTION	producing nitric oxide synthesis from arginine and molecular oxygen
	playing a role in neurogenesis
	role for IDO1 in the regulation of blood pressure, although the contribution of IDO1 to sepsis-induced hypotension is smaller that that of NOS2 (Hofmann 2010)
	role of NOS2 as a critical host factor regulating apoptosis during respiratory syncytial virus (RSV) infection
	immune-activated glial cells produced NOS2
	its expression is restricted to neurons in the healthy brain but is triggered in microglia upon inflammation
	is an important mediator in high-cholesterol diet (HCD)-induced liver fibrosis
	NOS2 is calcium-independent and is inducible
	is a major signaling molecule involved in innate immunity
	is a novel negative regulator of hematopoietic cell migration and prevents egress of hematopoietic stem/progenitor cells (HSPCs) into peripheral blood (PB) during mobilization
	crucial role of endogenous NOS2 in promoting optimal IL2 production, proliferation and glycolysis of gamma-delta T cells that may contribute to their regulation at steady state
	is necessary for the microbicidal activity of macrophages
	regulates a number of cellular processes in these cell types without exerting toxicity

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development , immunity/defense , inflammation , electron transport

text	tumoricidal and bactericidal
	electron carrier
	neurogenesis

PATHWAY

metabolism

aminoacid

signaling

	arginine catabolism
	NOS2 and IDO1 pathways are implicated in antimicrobial activities, antitumor defense, neuropathology and immune regulation (Hofmann 2010)

a component	specific aminoacids critical for dimerization and catalytic activity (in the domain encoded by exons 8 and 9)
	dimeric form of the enzyme stabilized by tetrahydrobiopterin (BH4)

INTERACTION

DNA

RNA

small molecule	cofactor,
	heme
	FAD
	FMN
	Ca2+
	Fe2+
	NADP
	Zn2+

protein	calmodulin binding protein, Ca2+ dependent
	with CEBPB through the AABS promoter response element
	binding to SLC9A3R1
	phosphorylated TP63 induces transcription of ADRM1, leading to NOS2 protein degradation
	SPSB1, SPSB2, SPSB4 can induce the subcellular redistribution of NOS2 from dense regions to diffused expression in a SOCS box-dependent manner
	POU2F1 cooperates with the TATA binding initiation complex to control rapid transcription of NOS2
	XPO1 and EIF4E seem to play an important role in the nucleocytoplasmic export of human NOS2 mRNA
	positive feedback regulation of inducible nitric-oxide synthase expression by RAS protein S-nitrosylation
	RELA and STAT1 cooperate to control NOS2 gene transcription in response to proinflammatory cytokines by a coactivator exchange mechanism
	required for plasma cells (PCs)to respond to some prosurvival mediators associated with bone marrow stromal cells and at least one mediator, IL6, fed directly into this pathway by inducing NOS2
	IGF1 inhibits cells apoptosis in pulmonary artery smooth muscle cells (PASMC) by activating the MAPK14-NOS2 transduction pathway
	IRF1-NOS2 axis is a crucial regulator of cardiac remodeling
	MMP12 regulates adipose tissue expansion, insulin sensitivity, and expression of NOS2
	coactivator EP300 mediates cytokine-induced NOS2 transactivation by forming a distant DNA loop between its enhancer and core promoter region
	is a potential target of the histone methyltransferase EZH2 which mediates trimethylation of histone 3 at lysine 27 (H3K27me3)
	during transdifferentiation, innate immune activation increases NOS2 generation of NO to S-nitrosylate RING1, a key member of the polycomb repressive complex
	KLF4 is important for regulating the expression of NOS2 by TNF in human synoviocytes
	FYN has likely a regulatory role in NOS2 expression in astrocytes during neuroinflammatory responses
	SPSB1 and SPSB2 are key physiological regulators of NOS2

cell & other

REGULATION

activated by

KLF5 (KLF5 activates NOS2 gene transcription and is involved in vascular inflammatory injury and remodeling)

induced by	endotoxins, cytokines
		HMGA1
		cytokines and endotoxin with IDO1 in the vascular endothelium (Hofmann 2010)

inhibited by

aspirin

repressed by	ELK3
		aspirin

Other	regulated by calcium/calmodulin
	regulation of NOS2 induction by the interaction between the spliced and unspliced forms of XBP1 in response to ER stress
	is regulated on the expressional level mostly by post-transcriptional mechanisms modulating the mRNA stability

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in astrocytes in the optic nerve head and lamina cribosa of glaucomatous eyes (neurotoxic effect) tumoral     --over   of NOS2 expression in borderline and malignant epithelial ovarian tumours indicates its involvement in the development and progression of epithelial ovarian cancer (EOC), and its increased expression in less differentiated cancers suggests their association with poor prognosis in this category of tumours tumoral     --over   in pancreatic ductal adenocarcinoma (PDAC)

Susceptibility

cerebral malaria and severe malarial anemia to multiple sclerosis to pulmonary tuberculosis

Variant & Polymorphism SNP	promoter C1173T protecting against severe malaria
	allele 1659 T marker of cerebral malaria
	variant increasing the risk of multiple sclerosis
	variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1 (NOS2A rs2248814 and IFNGR1 rs1327474 and NOS2A rs944722 and IFNGR1 rs1327474 )(Velez 2009)

Candidate gene	allele sharing with NOS2A and other markers of chromosome 17 (D17S949, D17S799)
	candidate for MS susceptibility
Marker	potential relevance of NOS2 as a prognostic factor for glioma malignancy and recurrence
	NOS2 is a predictor of prognosis in early stage, resected PDAC patients
Therapy target
	System Type Disorder Pubmed cancer digestive pancreas targeting NOS2 may have potential therapeutic value in pancreatic ductal adenocarcinoma cancer angiogenesis   Therapeutic manipulation of iNOS levels may remove a critical cytoprotective mechanism of importance in tumour angiogenesis

ANIMAL & CELL MODELS