NLRP9

Summary

NLRP9 (NLR family pyrin domain containing 9, HGNC:22941) is a protein-coding gene on chromosome 19q13.42, encoding NACHT, LRR and PYD domains-containing protein 9 (Q7RTR0). As the sensor component of the NLRP9 inflammasome, plays a crucial role in innate immunity and inflammation.

The protein encoded by this gene belongs to the NALP protein family. Members of the NALP protein family typically contain a NACHT domain, a NACHT-associated domain (NAD), a C-terminal leucine-rich repeat (LRR) region, and an N-terminal pyrin domain (PYD). This protein may play a regulatory role in the innate immune system as similar family members belong to the signal-induced multiprotein complex, the inflammasome, that activates the pro-inflammatory caspases, caspase-1 and caspase-5.

Source: NCBI Gene 338321 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 175 total
• MANE Select transcript: NM_176820

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22941
Approved symbol	NLRP9
Name	NLR family pyrin domain containing 9
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	NOD6, PAN12, CLR19.1
Ensembl gene	ENSG00000185792
Ensembl biotype	protein_coding
OMIM	609663
Entrez	338321

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000332836, ENST00000590200

RefSeq mRNA: 1 — MANE Select: NM_176820 NM_176820

CCDS: CCDS12934

Canonical transcript exons

ENST00000332836 — 9 exons

Exon	Start	End
ENSE00001290220	55716728	55716898
ENSE00001296963	55712420	55712590
ENSE00001297122	55738095	55738402
ENSE00001298283	55729831	55729992
ENSE00001310082	55715055	55715225
ENSE00001311490	55708438	55709044
ENSE00001316828	55711800	55711970
ENSE00001318104	55731999	55733550
ENSE00001325220	55723980	55724144

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 98.80.

Top tissues by expression

211 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.80	silver quality
oocyte	CL:0000023	97.46	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.64	gold quality
upper leg skin	UBERON:0004262	48.79	silver quality
buccal mucosa cell	CL:0002336	48.60	gold quality
skin of hip	UBERON:0001554	48.50	silver quality
muscle layer of sigmoid colon	UBERON:0035805	45.57	gold quality
tibial artery	UBERON:0007610	44.76	gold quality
popliteal artery	UBERON:0002250	44.74	gold quality
body of stomach	UBERON:0001161	43.98	gold quality
prostate gland	UBERON:0002367	43.37	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
fundus of stomach	UBERON:0001160	42.30	gold quality
bone marrow	UBERON:0002371	41.74	gold quality
stomach	UBERON:0000945	41.73	gold quality
aorta	UBERON:0000947	41.50	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
colonic epithelium	UBERON:0000397	41.28	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
lower esophagus mucosa	UBERON:0035834	41.07	silver quality
right coronary artery	UBERON:0001625	41.05	silver quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
sural nerve	UBERON:0015488	40.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	40.95	gold quality
body of uterus	UBERON:0009853	40.92	silver quality
left uterine tube	UBERON:0001303	40.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting NLRP9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-4700-3P	97.74	68.64	1014
HSA-MIR-7112-3P	97.67	68.77	948
HSA-MIR-708-3P	97.50	68.67	1082
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-621	96.76	66.89	371
HSA-MIR-7108-5P	96.42	66.17	598

Literature-anchored findings (GeneRIF, showing 5)

• The Genetic variants located in NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. (PMID:30217166)
• Maternally contributed Nlrp9b expressed in human and mouse ovarian follicles contributes to early murine preimplantation development. (PMID:32399794)
• Crystal structure of the human NLRP9 pyrin domain suggests a distinct mode of inflammasome assembly. (PMID:32542665)
• Crystal structure of the human NLRP9 pyrin domain reveals a bent N-terminal loop that may regulate inflammasome assembly. (PMID:32542766)
• Somatic Mutation of NLRP Genes in Gastric and Colonic Cancers. (PMID:34257569)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nlrp9c	ENSMUSG00000040614
mus_musculus	Nlrp9a	ENSMUSG00000054102
mus_musculus	Nlrp9b	ENSMUSG00000060508
rattus_norvegicus	Nlrp9	ENSRNOG00000021913

Paralogs (20): NLRP2 (ENSG00000022556), NLRP1 (ENSG00000091592), NOD1 (ENSG00000106100), NLRC5 (ENSG00000140853), NLRP12 (ENSG00000142405), NLRP14 (ENSG00000158077), NLRP4 (ENSG00000160505), NLRX1 (ENSG00000160703), NLRP3 (ENSG00000162711), NOD2 (ENSG00000167207), NLRP7 (ENSG00000167634), NLRC3 (ENSG00000167984), NLRP5 (ENSG00000171487), NLRP13 (ENSG00000173572), NLRP6 (ENSG00000174885), CIITA (ENSG00000179583), NLRP8 (ENSG00000179709), NLRP11 (ENSG00000179873), NLRP10 (ENSG00000182261), PYDC2 (ENSG00000253548)

Protein

Protein identifiers

NACHT, LRR and PYD domains-containing protein 9 — Q7RTR0 (reviewed: Q7RTR0)

Alternative names: Nucleotide-binding oligomerization domain protein 6, PYRIN and NACHT-containing protein 12

All UniProt accessions (1): Q7RTR0

UniProt curated annotations — full annotation on UniProt →

Function. As the sensor component of the NLRP9 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens, including rotavirus, initiates the formation of the inflammasome polymeric complex, made of NLRP9, PYCARD and CASP1. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and release in the extracellular milieu. The active cytokines stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. NLRP9 inflammasome activation may be initiated by DHX9 interaction with viral double-stranded RNA (dsRNA), preferentially to short dsRNA segments.

Subunit / interactions. Sensor component of NLRP9 inflammasomes. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens, such as rotavirus, and play critical roles in innate immunity and inflammation. The core of NLRP9 inflammasomes consists of a signal sensor component (NLRP9), an adapter (ASC/PYCARD), which recruits an effector pro-inflammatory caspase (CASP1). Within the complex, NLRP9 and PYCARD interact via their respective DAPIN/pyrin domains. This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. Interacts with DHX9 upon rotavirus infection; this interaction may trigger inflammasome activation and inflammatory response.

Subcellular location. Cytoplasm. Inflammasome.

Tissue specificity. Expressed in ileum intestinal epithelial cells. Not detected in peripheral blood mononuclear cells. Expressed in cerebral endothelial cells and, at much lower levels, in brain pericytes.

Induction. In brain pericytes, up-regulated at the mRNA level in response to oxidative stress.

Similarity. Belongs to the NLRP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7RTR0-1	1	yes
Q7RTR0-2	2

RefSeq proteins (1): NP_789790* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR004020	DAPIN	Domain
IPR007111	NACHT_NTPase	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR041075	NOD1/2_WH	Domain
IPR041267	NLRP_HD2	Domain
IPR050637	NLRP_innate_immun_reg	Family

Pfam: PF02758, PF05729, PF13516, PF17776, PF17779

UniProt features (19 total): helix 6, repeat 6, domain 2, chain 1, splice variant 1, sequence variant 1, turn 1, binding site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6Z2G	X-RAY DIFFRACTION	1.95
7BSO	X-RAY DIFFRACTION	2.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7RTR0-F1	90.14	0.65

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 152–159

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 41 (showing top): GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DEFENSE_RESPONSE_TO_VIRUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_RESPONSE_TO_VIRUS, GOCC_CANONICAL_INFLAMMASOME_COMPLEX, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOBP_INTERLEUKIN_18_PRODUCTION, GOBP_PYROPTOTIC_INFLAMMATORY_RESPONSE

GO Biological Process (7): positive regulation of interleukin-18 production (GO:0032741), innate immune response (GO:0045087), regulation of inflammatory response (GO:0050727), defense response to virus (GO:0051607), pyroptotic inflammatory response (GO:0070269), immune system process (GO:0002376), inflammatory response (GO:0006954)

GO Molecular Function (3): ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), canonical inflammasome complex (GO:0061702)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inflammatory response	2
defense response	2
positive regulation of cytokine production	1
interleukin-18 production	1
regulation of interleukin-18 production	1
immune response	1
defense response to symbiont	1
regulation of defense response	1
regulation of response to external stimulus	1
response to virus	1
biological_process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytosol	1
protein-containing complex	1

Protein interactions and networks

STRING

457 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLRP9	MEFV	O15553	822
NLRP9	CASP1	P29466	821
NLRP9	NLRC4	Q9NPP4	629
NLRP9	NLRP1	Q9C000	625
NLRP9	NLRP6	P59044	594
NLRP9	AIM2	O14862	561
NLRP9	NLRC5	Q86WI3	510
NLRP9	GSDMD	P57764	503
NLRP9	NLRP3	Q96P20	469
NLRP9	NLRP4	Q96MN2	445
NLRP9	IL18	Q14116	404
NLRP9	GSDMA	Q96QA5	395
NLRP9	IFI16	Q16666	391
NLRP9	PYCARD	Q9ULZ3	375
NLRP9	OOEP	A6NGQ2	363

IntAct

2 interactions, top by confidence:

A	B	Type	Score
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (11): NLRP9 (Co-fractionation), NLRP9 (Co-fractionation), NLRP9 (Co-fractionation), NLRP9 (Co-fractionation), PSMD12 (Co-fractionation), NLRP9 (Synthetic Lethality), NLRP9 (Affinity Capture-MS), NLRP9 (Affinity Capture-MS), NLRP9 (Affinity Capture-MS), NLRP9 (Cross-Linking-MS (XL-MS)), TET3 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0G2JMD5, A1Z198, A3QJZ6, A3QJZ7, A6NGN4, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5G7, H0Y7S4, O60809, O60810, O60811, O60813, O95521, O95522, P0DUQ1, P0DUQ2, P78395, Q0GKD5, Q288C4, Q2LKU9, Q2LKV5, Q2LKW6, Q3TKR3, Q3UWY1, Q5SWL7, Q5SWL8, Q5TYX0, Q5VT98, Q5VTA0, Q5VWM3, Q5VWM4, Q5VWM6, Q5VXH4, Q5VXH5, Q66X05, Q66X19

Diamond homologs: A0A386CAB9, A1Z198, A6QLE5, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, O15553, P10775, P13489, P29315, P59044, P59045, P59046, Q0GKD5, Q288C4, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q3TKR3, Q63035, Q647I9, Q66X01, Q66X03, Q66X19, Q6B966, Q7RTR0, Q86W24, Q86W25, Q86W26, Q86W28, Q8BU40, Q8C6J9, Q8CCN1, Q8HZP9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

175 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	18
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1443 predictions. Top by Δscore:

Variant	Effect	Δscore
19:55709040:GCAGC:G	acceptor_gain	1.0000
19:55709041:CAGC:C	acceptor_gain	1.0000
19:55709041:CAGCC:C	acceptor_gain	1.0000
19:55709042:AGC:A	acceptor_gain	1.0000
19:55709043:GC:G	acceptor_gain	1.0000
19:55709043:GCC:G	acceptor_loss	1.0000
19:55709044:CC:C	acceptor_gain	1.0000
19:55709044:CCTGG:C	acceptor_loss	1.0000
19:55709045:C:CC	acceptor_gain	1.0000
19:55711794:ACTC:A	donor_loss	1.0000
19:55711798:A:AC	donor_gain	1.0000
19:55711798:AC:A	donor_gain	1.0000
19:55711798:ACC:A	donor_gain	1.0000
19:55711799:C:CC	donor_gain	1.0000
19:55711799:C:CG	donor_loss	1.0000
19:55711799:CC:C	donor_gain	1.0000
19:55711799:CCC:C	donor_gain	1.0000
19:55711966:GCAGC:G	acceptor_gain	1.0000
19:55711967:CAGC:C	acceptor_gain	1.0000
19:55711967:CAGCC:C	acceptor_gain	1.0000
19:55711971:C:CA	acceptor_loss	1.0000
19:55711971:C:CC	acceptor_gain	1.0000
19:55712466:A:C	donor_gain	1.0000
19:55716726:A:AC	donor_gain	1.0000
19:55716727:C:CC	donor_gain	1.0000
19:55716899:C:CC	acceptor_gain	1.0000
19:55723978:A:AC	donor_gain	1.0000
19:55723979:C:CC	donor_gain	1.0000
19:55723979:CAT:C	donor_gain	1.0000
19:55724140:TAAAT:T	acceptor_gain	1.0000

AlphaMissense

6586 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:55738294:C:A	K27N	0.989
19:55738294:C:G	K27N	0.989
19:55723983:A:G	L719P	0.985
19:55729970:A:G	W619R	0.981
19:55729970:A:T	W619R	0.981
19:55715213:G:C	C781W	0.980
19:55716802:A:C	N752K	0.980
19:55716802:A:T	N752K	0.980
19:55716818:A:G	L747P	0.980
19:55712465:A:G	L876S	0.977
19:55712510:A:G	L861P	0.975
19:55711890:A:G	L918P	0.974
19:55716816:A:G	S748P	0.974
19:55732502:G:C	F443L	0.972
19:55732502:G:T	F443L	0.972
19:55732504:A:G	F443L	0.972
19:55716812:A:G	L749S	0.971
19:55711968:A:G	L892P	0.970
19:55733326:A:G	W169R	0.970
19:55733326:A:T	W169R	0.970
19:55733358:T:A	K158I	0.969
19:55712588:A:G	L835S	0.968
19:55715215:A:G	C781R	0.968
19:55715129:A:C	N809K	0.967
19:55715129:A:T	N809K	0.967
19:55712504:A:T	L863H	0.966
19:55729968:C:A	W619C	0.964
19:55729968:C:G	W619C	0.964
19:55733294:G:C	F179L	0.964
19:55733294:G:T	F179L	0.964

dbSNP variants (sampled 300 via entrez): RS1000093791 (19:55721549 G>A), RS1000169356 (19:55717111 G>A,T), RS1000196061 (19:55738556 A>C), RS1000290200 (19:55712330 C>A,T), RS1000317342 (19:55735656 T>C), RS1000342224 (19:55712113 C>CCTGGGGGA), RS1000374404 (19:55725620 G>A), RS1000566148 (19:55719973 G>C), RS1000580867 (19:55719548 G>C), RS1000697753 (19:55729539 T>A), RS1000739271 (19:55734288 T>G), RS1000739543 (19:55724836 T>A), RS1000750092 (19:55729428 T>TCCTGTGC), RS1000982909 (19:55724589 ATTTTT>A,ATTT,ATTTT,ATTTTTT,ATTTTTTT), RS1000991056 (19:55710947 A>G)

Disease associations

OMIM: gene MIM:609663 | disease phenotypes: MIM:310500

GenCC curated gene-disease

Mondo (1): congenital stationary night blindness (MONDO:0016293)

Orphanet (1): Congenital stationary night blindness (Orphanet:215)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001850_49	Major depressive disorder	6.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536122	Night blindness, congenital stationary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — NOD-like receptor family

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
Asian ginseng	affects cotreatment, decreases expression	1
bisphenol A	decreases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Diethylhexyl Phthalate	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Methapyrilene	increases methylation	1
Tobacco Smoke Pollution	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02909985	Not specified	COMPLETED	Visual Activity Evoked by Infrared in Humans After Dark Adaptation