GNLY

Summary

GNLY (granulysin, HGNC:4414) is a protein-coding gene on chromosome 2p11.2, encoding Granulysin (P22749). Antimicrobial protein that kills intracellular pathogens.

The product of this gene is a member of the saposin-like protein (SAPLIP) family and is located in the cytotoxic granules of T cells, which are released upon antigen stimulation. This protein is present in cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, and it has antimicrobial activity against M. tuberculosis and other organisms. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 10578 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_006433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4414
Approved symbol	GNLY
Name	granulysin
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	NKG5, LAG-2, D2S69E, TLA519
Ensembl gene	ENSG00000115523
Ensembl biotype	protein_coding
OMIM	188855
Entrez	10578

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 retained_intron, 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000263863, ENST00000409696, ENST00000464298, ENST00000470974, ENST00000482900, ENST00000488945, ENST00000489214, ENST00000489980, ENST00000491234, ENST00000524600, ENST00000526018, ENST00000531685, ENST00000533041, ENST00000534351, ENST00000905733

RefSeq mRNA: 3 — MANE Select: NM_006433 NM_001302758, NM_006433, NM_012483

CCDS: CCDS1984, CCDS46354, CCDS77430

Canonical transcript exons

ENST00000263863 — 5 exons

Exon	Start	End
ENSE00000799876	85697506	85697677
ENSE00001886592	85698564	85698852
ENSE00003547576	85695320	85695423
ENSE00003640002	85695958	85696056
ENSE00003903747	85694358	85694470

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 99.94.

FANTOM5 (CAGE): breadth broad, TPM avg 36.9600 / max 9563.5253, expressed in 306 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21244	15.9781	216
21243	12.6864	198
21245	7.6737	163
21249	0.2141	79
21247	0.1279	41
21250	0.0844	24
21246	0.0824	36
21248	0.0522	24
21242	0.0416	17
21241	0.0192	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.94	gold quality
blood	UBERON:0000178	97.83	gold quality
decidua	UBERON:0002450	94.92	gold quality
spleen	UBERON:0002106	94.40	gold quality
bone marrow cell	CL:0002092	91.89	gold quality
apex of heart	UBERON:0002098	90.87	gold quality
upper lobe of left lung	UBERON:0008952	90.81	gold quality
leukocyte	CL:0000738	88.48	gold quality
bone marrow	UBERON:0002371	88.42	gold quality
right lung	UBERON:0002167	88.08	gold quality
upper lobe of lung	UBERON:0008948	88.08	gold quality
right lobe of liver	UBERON:0001114	87.46	gold quality
mononuclear cell	CL:0000842	87.41	gold quality
monocyte	CL:0000576	87.04	gold quality
lymph node	UBERON:0000029	85.15	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.95	gold quality
endometrium	UBERON:0001295	83.13	gold quality
omental fat pad	UBERON:0010414	82.73	gold quality
peritoneum	UBERON:0002358	82.66	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.27	gold quality
vermiform appendix	UBERON:0001154	81.55	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.43	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.88	gold quality
gastrocnemius	UBERON:0001388	80.86	gold quality
gall bladder	UBERON:0002110	80.71	gold quality
muscle of leg	UBERON:0001383	79.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.29	silver quality
lung	UBERON:0002048	79.16	gold quality
periodontal ligament	UBERON:0008266	78.92	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.64	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 39.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	102839.99
E-MTAB-6701	yes	99815.14
E-MTAB-6678	yes	73866.44
E-MTAB-6505	yes	56019.97
E-HCAD-23	yes	39320.39
E-MTAB-10287	yes	37360.91
E-GEOD-139324	yes	19429.67
E-CURD-120	yes	19323.65
E-MTAB-6653	yes	15833.63
E-CURD-95	yes	15600.73
E-MTAB-8207	yes	13062.81
E-GEOD-70580	yes	12839.81
E-MTAB-6308	yes	12358.69
E-GEOD-149689	yes	12223.94
E-HCAD-4	yes	12030.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, GLI2, JUN, STAT5A, ZGLP1

miRNA regulators (miRDB)

14 targeting GNLY, 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-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-1247-3P	83.69	63.18	99

Literature-anchored findings (GeneRIF, showing 40)

• Peptides encoded by this gene display antimicrobial activity against S. typhimurium, L. monocytogenes, E. coli, S. aureus, C. neoformans, C. albicans, L. major, and M. tuberculosis. (PMID:10644038)
• This molecule activates a pathway of CTL- and NK cell-mediated death via disruption of cell and mitochondrial membranes. This is a distinct pathway from granzyme- and death receptor-induced apoptosis. (PMID:11418670)
• The megakaryoblastic leukemia cell line CMK, from a Down’s syndromept, expressed granulysin mRNA, suggesting that GNLY is occasionally present in immature multilineage cells or may be characteristic of leukemic cells obtained from Down’s syndrome pts. (PMID:12145461)
• Up-regulation of granulysin in primary CD8 T cells correlates with the acquisition of anticryptococcal activity, which can be blocked by specific inhibition of granulysin. (PMID:12421959)
• Sequence analysis of this gene do not support it as a candidate gene for familial hemophagocytic lymphohistiocytosis. (PMID:12483306)
• Data report the initial crystal structure of selenomethionyl granulysin by MAD phasing at 2A resolution. (PMID:12488100)
• Granulysin is detected in a granular pattern in the cytoplasm of alpha GalCer-activated NKT cells consistent with their presence within cytotoxic granules and suggests that these cells can mediate antimicrobial activity. (PMID:12626573)
• mRNA expression measurement of granulysin in urinary cells of renal allograft ents allows the early noninvasive detection of ongoing acute rejection. (PMID:15223905)
• granulysin was found exclusively in endosomal-phagosomal vesicles; lipid raft microdomains, enriched in the immunological synapse, may thus enhance uptake and transfer of granulysin into bacterial infected host cells (PMID:15778384)
• Granulysin not only contributes to innate immunity but also to adaptive immunity as it attracts and activates human monocytes, dendritic, natural killer (NK) and T cells. (PMID:15843520)
• Granulysin expression in CD8 cells seems to be correlated with steroid resistance in polymyositis (PMID:16980658)
• These cells use granulysin as the effector molecule, and priming is dysregulated in HIV-infected patients, which results in defective microbicidal activity (PMID:17038537)
• This study shows that the regulation of granulysin synthesis in response to IL-2 or bacterial antigen stimulation occurs at several levels: RNA expression, extensive alternative splicing and posttranslational processing. (PMID:17596262)
• Serum granulysin is elevated in patients with hemophagocytic lymphohistiocytosis (PMID:18192122)
• study found PI3K & STAT5 signaling pathways are required for granulysin expression & IL-2Rbeta induction & IL-2Rbeta induction is a prerequisite for granulysin expression; both signaling pathways are defective in CD4+ T cells from HIV-infected patients (PMID:18490721)
• Increased expression in pbmc and elevated serum levels correlated with the severity of primary biliary cirrhosis (PMID:18584314)
• granulysin is involved in spontaneous abortion. (PMID:18688023)
• Granulysin in the blister fluids was a 15-kDa secretory form (PMID:19029983)
• serum granulysin is a novel parameter of patients cancer immunity (PMID:19106590)
• Results demonstrate the localization and effect of intracellularly expressed granulysin on non-native cancer cells and indicate its potential utility in gene therapy for cancer. (PMID:19111751)
• High granulysin mrna expression is associated with systemic anaplastic large cell lymphoma. (PMID:19243819)
• Granulysin can target lysosomes to induce partial release of lysosomal contents into the cytosol; relocalized lysosomal cathepsin B can process Bid to active tBid to cause cytochrome c and apoptosis-activating factor release from mitochondria. (PMID:19454696)
• HIV-1 infection of peripheral blood mononuclear cells may reduce the antimicrobial profile of activated CD8+ T cells by disrupting signaling events that are critical for the induction of granulysin. (PMID:19687290)
• GLS/IL-12-modified Mycobacterium smegmatis as a novel anti-tuberculosis immunotherapeutic vaccine. (PMID:19861007)
• Both 9- and 15-kDa forms of recombinant GNLY-induced in vitro chemotaxis and activation of both human and mouse dendritic cells. (PMID:20660289)
• these data provide details about the complex regulation leading to granulysin expression and anticryptococcal activity in primary CD4(+) T cells. (PMID:20889547)
• Cytotoxic T- and natural killer (NK) cell-delivered transgenic granulysin induces endoplasmic reticulum stress, activating caspase-7 and distinct apoptotic pathways in target cells. (PMID:21296981)
• Gene expression profiles of monocytes cultured with 15 kDa Granulysin or GM-CSF for 4, 12, 24 and 48 hours were analysed to unravel both similarities and differences between the effects of these stimulators. (PMID:21501511)
• All these data clearly show the abundant expression and spontaneous secretion of GNLY by decidual NK cells during first trimester pregnancy. (PMID:21623991)
• Granulysin is expressed at different levels in multiple cutaneous adverse drug reactions both by NKp46(+) cells and by CD8(+) T cells. (PMID:21819408)
• GNLY-expressing lymphocytes, probably attracted by IL-15, not only participate partially in myocardial cell apoptosis, but also hasten resolution of cardiac leukocyte infiltration in patients with myocardial infarction. (PMID:21967803)
• Findings suggest that Vgamma9Vdelta2 T cell-mediated production of granulysin as an underestimated immune effector in malaria. (PMID:22045985)
• Proliferating memory T cells (CFSE(low)CD4(+)CD45RO(+)) were identified as main source of granulysin and these cells expressed both central and effector memory phenotype (PMID:22216262)
• recombinant 15 kDa granulysin is not cytolytic but is a potent inducer of monocytic differentiation to dendritic cells (PMID:22586033)
• GNLY polymorphism genotypes and diplotypes were associated with the chronicity of HBV (PMID:22788687)
• Granulysin is closely associated with the characteristics of NK-cell neoplasms and serum granulysin may serve as a novel biomarker for these disorders. (PMID:22890551)
• study to determine: expression of GNLY at the gene and protein levels at the maternal-fetal interface, relationship(s) between GNLY and perforin, and GNLY secretion by stimulated NK cells (PMID:23399514)
• suggested that the alteration of circulating granulysin has potential function in host immune response against TB and HIV/TB coinfection (PMID:23801887)
• Serum granulysin levels were significantly elevated in both acute and chronic alopecia areata patients. (PMID:24035442)
• It was concluded taht granulysin induces apoptosis on hematological tumor cells and on cells from B-cell lymphocytic leukemia patients, opening the door to research on its use as a new anti-tumoral treatment. (PMID:24269628)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Granulysin — P22749 (reviewed: P22749)

Alternative names: Lymphokine LAG-2, Protein NKG5, T-cell activation protein 519

All UniProt accessions (3): B4E3H9, P22749, H0YDW8

UniProt curated annotations — full annotation on UniProt →

Function. Antimicrobial protein that kills intracellular pathogens. Active against a broad range of microbes, including Gram-positive and Gram-negative bacteria, fungi, and parasites. Kills Mycobacterium tuberculosis.

Subcellular location. Secreted.

Tissue specificity. Expressed in natural killer and T-cells.

Post-translational modifications. A 9 kDa form is produced by proteolytic processing of a 15 kDa protein.

Induction. By T-cell growth factor and IL2/interleukin-2.

Isoforms (2)

UniProt ID	Names	Canonical?
P22749-1	Long	yes
P22749-2	Short

RefSeq proteins (3): NP_001289687, NP_006424, NP_036615 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008138	SapB_2	Domain
IPR008139	SaposinB_dom	Domain
IPR011001	Saposin-like	Homologous_superfamily
IPR038847	Granulysin-like	Family

Pfam: PF03489

UniProt features (16 total): helix 6, sequence conflict 3, disulfide bond 2, signal peptide 1, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1L9L	X-RAY DIFFRACTION	0.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22749-F1	78.51	0.51

Functional residue map

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

Disulfide bonds (2): 69–132, 96–107

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803157	Antimicrobial peptides

MSigDB gene sets: 124 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, MODULE_45, MODULE_128, RICKMAN_METASTASIS_DN, MODULE_75, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, WONG_ENDMETRIUM_CANCER_DN, MODULE_171, GNF2_IL2RB, GOBP_HUMORAL_IMMUNE_RESPONSE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, chr2p11, GOBP_CELLULAR_DEFENSE_RESPONSE

GO Biological Process (5): cellular defense response (GO:0006968), killing of cells of another organism (GO:0031640), defense response to bacterium (GO:0042742), defense response to fungus (GO:0050832), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), phagocytic vesicle lumen (GO:0097013), cytolytic granule (GO:0044194)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	3
cell killing	1
disruption of cell in another organism	1
response to bacterium	1
response to fungus	1
antimicrobial humoral response	1
binding	1
cellular anatomical structure	1
phagocytic vesicle	1
endocytic vesicle lumen	1
lysosome	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GNLY	BCL2L1	psi-mi:“MI:0915”(physical association)	0.560
GNLY	DERL3	psi-mi:“MI:0915”(physical association)	0.560
GNLY	YPEL5	psi-mi:“MI:0914”(association)	0.530
GNLY	PRKCI	psi-mi:“MI:0914”(association)	0.350
GNLY	GTPBP10	psi-mi:“MI:0914”(association)	0.350
BCL2L1	GNLY	psi-mi:“MI:0915”(physical association)	0.000
DERL3	GNLY	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): GNLY (Biochemical Activity), GNLY (Two-hybrid), BCL2L1 (Two-hybrid), MKLN1 (Affinity Capture-MS), RANBP9 (Affinity Capture-MS), LRRC1 (Affinity Capture-MS), RBM27 (Affinity Capture-MS), RBM23 (Affinity Capture-MS), PHF10 (Affinity Capture-MS), C1QBP (Affinity Capture-MS), UBAC1 (Affinity Capture-MS), RANBP10 (Affinity Capture-MS), GID8 (Affinity Capture-MS), TRPM3 (Affinity Capture-MS), MAEA (Affinity Capture-MS)

ESM2 similar proteins: A0A096P2H6, A0A0D9S1R4, A2APA5, A9CBA0, P06740, P06759, P0DKU6, P0DKW1, P0DKW2, P0DKW3, P0DKW4, P0DKY3, P0DML4, P0DML5, P0DML6, P0DMN8, P0DOC4, P0DP53, P0DTG9, P0DTH0, P0DTH1, P0DTH2, P0DTH3, P0DTH4, P0DUP5, P0DUP6, P22749, P33622, P35225, P55056, P55057, P55797, Q0VCT2, Q13790, Q3SYR5, Q3ZRW9, Q5HZE8, Q5JTB6, Q5JX69, Q5JX71

Diamond homologs: P22749, Q29075, Q8HZQ3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

896 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85695421:CAGG:C	donor_loss	1.0000
2:85695422:AGGT:A	donor_loss	1.0000
2:85695423:GGT:G	donor_loss	1.0000
2:85695424:G:GC	donor_loss	1.0000
2:85695425:T:A	donor_loss	1.0000
2:85695952:T:TA	acceptor_gain	1.0000
2:85695955:CAG:C	acceptor_loss	1.0000
2:85695956:A:AG	acceptor_gain	1.0000
2:85695956:AG:A	acceptor_gain	1.0000
2:85695956:AGG:A	acceptor_gain	1.0000
2:85695957:G:GT	acceptor_gain	1.0000
2:85695957:GG:G	acceptor_gain	1.0000
2:85695957:GGG:G	acceptor_gain	1.0000
2:85695957:GGGT:G	acceptor_gain	1.0000
2:85696053:CCAG:C	donor_loss	1.0000
2:85696054:CAG:C	donor_loss	1.0000
2:85696055:AGG:A	donor_loss	1.0000
2:85696056:GGT:G	donor_loss	1.0000
2:85696057:GT:G	donor_loss	1.0000
2:85696058:T:G	donor_loss	1.0000
2:85695314:CCTCA:C	acceptor_loss	0.9900
2:85695315:CTCAG:C	acceptor_loss	0.9900
2:85695317:CA:C	acceptor_loss	0.9900
2:85695318:A:T	acceptor_loss	0.9900
2:85695338:T:TA	acceptor_gain	0.9900
2:85695424:G:GG	donor_gain	0.9900
2:85695956:AGGGT:A	acceptor_gain	0.9900
2:85695957:GGGTG:G	acceptor_gain	0.9900
2:85697489:T:TA	acceptor_gain	0.9900
2:85695318:A:AG	acceptor_gain	0.9800

AlphaMissense

926 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85697578:T:C	F110L	0.888
2:85697580:C:A	F110L	0.888
2:85697580:C:G	F110L	0.888
2:85697513:T:A	V88D	0.855
2:85696019:T:A	V73D	0.829
2:85697644:T:A	C132S	0.807
2:85697645:G:C	C132S	0.807
2:85697569:T:A	C107S	0.806
2:85697570:G:C	C107S	0.806
2:85697603:T:A	V118D	0.805
2:85697579:T:C	F110S	0.801
2:85697521:G:C	A91P	0.797
2:85697559:G:C	W103C	0.795
2:85697559:G:T	W103C	0.795
2:85697536:T:A	C96S	0.781
2:85697537:G:C	C96S	0.781
2:85697615:T:A	L122H	0.779
2:85697645:G:A	C132Y	0.774
2:85697579:T:G	F110C	0.770
2:85696016:T:A	I72K	0.767
2:85697569:T:C	C107R	0.761
2:85697570:G:A	C107Y	0.758
2:85697536:T:C	C96R	0.756
2:85697571:C:G	C107W	0.745
2:85696008:T:G	C69W	0.742
2:85696006:T:C	C69R	0.737
2:85697642:T:C	I131T	0.736
2:85697537:G:A	C96Y	0.726
2:85697524:G:C	A92P	0.722
2:85696028:T:C	L76P	0.716

dbSNP variants (sampled 300 via entrez): RS1000111433 (2:85693281 G>A), RS1000163737 (2:85693535 T>C), RS1000436291 (2:85698946 C>T), RS1000461846 (2:85698341 C>A), RS1000750824 (2:85693637 A>G), RS1001517665 (2:85699351 T>C), RS1002373503 (2:85695250 C>A,G), RS1002457512 (2:85697138 C>G,T), RS1002511330 (2:85697419 A>G,T), RS1003520169 (2:85695972 C>A), RS1003952972 (2:85699230 C>A,G,T), RS1004351728 (2:85693705 C>G,T), RS1004595045 (2:85693303 C>T), RS1005401445 (2:85692612 C>A,T), RS1005953218 (2:85696778 A>T)

Disease associations

OMIM: gene MIM:188855 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
bathocuproine sulfonate	affects cotreatment, decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
licochalcone B	increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Aspirin	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Dichlorvos	decreases expression	1
Diuron	decreases expression	1
Mercury	increases expression	1
Nickel	increases expression	1
Ozone	increases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression, decreases reaction	1
Dronabinol	increases expression	1
Ziram	decreases expression	1
Ionomycin	affects cotreatment, decreases expression, decreases reaction	1

Clinical trials (associated diseases)

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