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FLASH GENE

Symbol

NLRC4

contributors: mct - updated : 04-04-2018

HGNC name	NLR family, CARD domain containing 4
HGNC id	16412

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	AIFEC autoinflammation with infantile enterocolitis FCAS4 Familial cold autoinflammatory syndrome 4
Location	2p22.3      Physical location : 32.449.517 - 32.490.801
Synonym name	ICE-protease activating factor
	CARD, LRR and NACHT domain containing protein
	caspase recruitment domain family, member 12
	nucleotide-binding oligomerization domain, leucine rich repeat and CARD domain containing 4
Synonym symbol(s)	CLAN, IPAF1, CLANA, CLANB, CLANC, CLAND, IPAF, CLAN1, CARD12, CLR2.1

DNA

TYPE	like-sequence
STRUCTURE	41.29 kb     9 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_021209 9 - 3385 116.2 1024 - 2001 11472070 CLAN-A NM_001302504 8 splicing 1390 NP_001289433 40.6 359 . ubiquitous . highly in lung, spleen 2001 11472070 CLAN-B CLAN-C - splicing 768 17.5 156 absent in normal tissue 2001 11472070 CLAN-D - splicing 578 10 92 only in brain 2001 11472070 NM_001199139 9 - 3254 - 1024 - 2001 11472070 NM_001199138 9 - 3371 - 1024 - 2001 11472070

EXPRESSION

Type	ubiquitous

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 large intestine colon       salivary gland       highly Endocrine adrenal gland       moderately Lymphoid/Immune spleen       moderately Homo sapiens Nervous brain         Reproductive male system prostate       Respiratory lung         Urinary bladder       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte Blood/Hematopoietic monocyte

cell lineage
cell lines	monocyte cells lines
fluid/secretion	blood

at STAGE

physiological period

fetal, pregnancy

Text	placenta, liver

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal CARD domain
	a leucine rich repeat (LRR) repeat
	a NACHT domain
	13 leucine rich repeat at the C terminus (LRR)
	SAM domain

HOMOLOGY

interspecies	ortholog to rattus Card12
	ortholog to murine Card12

intraspecies

homolog to APAF1

Homologene

FAMILY	CED4 family
	NOD-like receptor family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton,intermed filament
	intracellular,nucleus,nucleoplasm

basic FUNCTION	playing a regulatory role in the processes of inflammation and cell death stimuli
	involved in activation of CASP1 in response to proinflammatory and apoptotic stimuli
	activator of caspase 1 in TP53-dependent apoptosis
	playing a role in the promotion of apoptosis
	maybe involved in sensing more than one bacterial molecule and may participate in several immune complexes
	potential role for ubiquitination of NLRC4 that is enabled by its interaction with PSMC5, leading to caspase 8 activation and cell death
	activates caspase 1 in response to bacterial virulence factors including type III and IV secretion systems (T3SS and T4SS)
	redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella
	innate immune recognition of flagellin is shared by transmembrane TLR5 and cytosolic NLRC4/NAIP
	activates CASP1 and downstream inflammatory response upon sensing cytosolic presence of flagellin during bacterial infection
	acts as an adaptor through which inflammasome activation signals generated from different NAIP receptors are transduced to CASP1
	intracellular receptors, such as NLRP1, NLRP3, NLRP6 and NLRC4, which mediate the assembly of inflammasome complexes leading to the activation of procaspase-1
	is a cytosolic NOD (nucleotide binding and oligomerization domain)-like receptor (NLR) that can trigger inflammasome formation in response to bacterial flagellin, an immunodominant antigen in the intestine
	importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases
	NLRC4-driven IL1B production is critical for the progression of Diabetic Nephropathy
	NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an lysophosphatidylcholine (LPC)-induced inflammasome and are important in astrogliosis and microgliosis
	NLRC4 stimulation leads to CASP1 activation followed by a rapid lytic cell death known as pyroptosis

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

immunity/defense

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	activating procaspase 1
	NFKB regulators (BCL10, CARD15)
	PYCARD
	Nod2
	NALP1 (NAC)
	PSMC5 binds to AAs 91-253 of NLRC4, which is also the region that the LRR domain binds to, potentiating cell death induced by NLRC4 and LRR-domain-deleted NLRC4, and co-expression of PSMC5 and NLRC4 induces CASP8-dependent cell death
	interacting with NAIP (NAIP regulates the apparent specificity of the NLRC4 inflammasome for distinct bacterial ligands)
	PYCARD connects pathogen/danger sensors such as NLRP3 and NLRC4 with caspases and is involved in inflammation and cell death
	flagellin recognition by NAIP stimulates the physical association between NAIP and NLRC4, thereby signalling downstream CASP1 activation
	ARRB1 plays a critical role in the assembly and activation of two major canonical inflammasomes, NLRC4, NLRP3
	activation of NLRC4 by bacterial flagellin downregulated the flagellin-induced and TLR5-mediated immune responses against flagellin
	NLRC4 interacts with PSMC5 and induces CASP8-mediated cell death
	IRF8 is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium
	IRF8 is a critical regulator of NLR family apoptosis inhibitory proteins (NAIPs) and NLRC4 inflammasome activation for defense against bacterial infection

cell & other

REGULATION

Other

is activated as part of the innate immune response to a range of intracellular bacteria, including S. typhimurium and Legionella pneumophila

ASSOCIATED DISORDERS

corresponding disease(s)

FCAS4 , AIFEC

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   mRNA levels of NLRC4, NLRP12, and IL1B were significantly upregulated in Kawasaki disease (KD) patients compared to the controls

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology acquired   NLRC4 and AIM2 inflammasomes are potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain

ANIMAL & CELL MODELS

transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis