GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa)

2009-10-01   Nathalie Britzen-Laurent , Michael Stürzl 

Division of Molecular, Experimental Surgery, Department of Surgery, Friedrich-Alexander University, Schwabachanlage 10, 91054 Erlangen, Germany

Identity

HGNC
LOCATION
1p22.2
LOCUSID
ALIAS
-
FUSION GENES

DNA/RNA

Description

The GBP1 gene consists of 11 exons (ranging from 102 to 1164 bp) and 10 introns. The coding sequence starts in the second exon.

Transcription

Only one variant mRNA has been described for GBP-1 (Accession Number: NM_002053). This mRNA is 3050 bp long with a coding sequence of 1779 bp. Four polymorphisms have been described for GBP-1: c.232A>G (codon 78 Ile>Val), c.498G>C (codon 166 Glu>Asp), c.1046C>G (codon 349 Thr>Ser), c.1226C>G (codon 409 Ala>Gly).

Pseudogene

A pseudogene has been identified for GBP1 (LOC400759 alias FLJ17004) on chromosome 1 (1p22.2, chro 1: 89645826-89663081, according to hg18-Mar_2006). Two pseudogenes have also been described in the mouse (pseudomGbp1 and pseudomGbp2).

Proteins

Atlas Image
A schematic representation of the domain structure and the three-dimensional structure of GBP-1. GBP-1 consists of a globular domain (residues 1 to 278), which contains the GTP binding and hydrolysis domains, and of a helical domain (residues 279 to 593) terminated by a polybasic sequence and an isoprenylation motif (CAAX). C= Cysteine, A= aliphatic acid, X= any amino-acid (here a serine, specifically recognized by a farnesyl-transferase).

Description

GBP-1 belongs to the class of large GTPases that contains, in addition to the GBPs, three further groups of proteins, which share structural and biochemical properties: the dynamins, the Mx proteins and the atlastins. GBP-1 has a molecular weight of 67 kDa and its crystal structure has revealed the presence of two domains: (1) a N-terminal globular alpha/beta domain harbouring the GTPase activity and (2) a long C-terminal part organized in an index finger-like domain composed exclusively of seven alpha-helices (alpha7 - alpha13). The domains are connected by a short intermediate region consisting of one alpha-helix and a short two-stranded beta-sheet. In addition, GBP-1 harbours a C-terminal CAAX isoprenylation motif. GTPases typically harbour three classical GTP-binding domains: the phosphate-binding P-loop GXXXXGK(S/T), the phosphate- and Mg2+-binding DXXG motif (G, glycine; K, lysine; S, serine; D, aspartic acid; T, threonine; and X, any amino acid) and the guanine nucleotide-specificity providing (N/T)KXD motif (N, asparagine). In GBP-1 the classical (N/T)KXD motif is substituted by a conserved arginine-aspartic acid (RD)-motif (TLRD, with L, leucine and R, arginine).

Expression

GBP-1 was initially shown to be among the most highly induced proteins in human fibroblasts exposed to interferon (IFN)-gamma. Subsequently, it was reported that in vitro hGBP-1 expression can be induced by IFN-gamma in many different cell types including endothelial cells, fibroblasts, keratinocytes, B-cells, T-cells or peripheral blood mononuclear cells. In vivo expression of hGBP-1 has been predominantly detected in inflammatory tissues and has been found to be associated almost exclusively with endothelial cells and monocytes. It has been shown subsequently that hGBP-1 expression in endothelial cells is also induced by other pro-inflammatory cytokines such as IFNalpha, TNFalpha and IL1alpha/IL1beta. Many other cytokines (IL-4, IL-6, IL-10, IL-18), chemokines (MCP-1, PF4) or growth factors (angiopoietin-2, PDGF B/B) tested did not affect GBP-1 expression in these cells. Interestingly, the two major angiogenic growth factors (AGF: bFGF, VEGF) are able to inhibit the expression of GBP-1 induced by inflammatory cytokines.

Localisation

The localization of GBP-1 is primarily cytosolic and its distribution is granular. Plasma membrane association at the level of tight junctions has also been described. In addition, GBP-1 has been shown to be secreted from IFN-gamma-stimulated endothelial cells through a non-classical secretion pathway.

Function

GTPase activity
GBP-1 can bind the three nucleotides GTP, GDP and GMP with a relative low affinity (Kd mant-GMP=0,53 μM, Kd mant-GDP=2,4 μM, Kdmant-GppNHp=1,1 μM). GBP-1 has however the ability to hydrolyse GTP to both GDP and GMP with a high hydrolysis rate (max 95 min-1). At physiological temperature GMP is the major product (90%) of hGBP1. On the contrary to small GTPases like Ras, GBP-1 does not require the presence of GEF (GTP exchange factor) or GAP (GTPase activating protein) proteins for its GTPase activity. In the case of GBP-1, the GTP hydrolysis is self-stimulated by oligomerization of the protein.
GBP-1 is involved in IFN-gamma response, either in infection or in inflammation.

Homology

The human GBP family comprises 7 highly homologous members, all located on the chromosome 1. GBP-1 is to 77% similar to GBP-2, 88% to GBP-3, 56% to GBP-4, 68% to GBP-5, 54% to GBP-6 and 56% to GBP-7. Homologues have been found in various species like zebrafish, chimpanzee (99% homology), rat, dog or mouse. GBP-1 shares 59% of homology with murine GBP-1 and murine GBP-2.

Mutations

Note

No somatic or germline mutations have yet been reported for human GBP-1.

Implicated in

Entity name
Infection
Note
GBP-1 exhibits antiviral activity against vesicular stomatitis virus and encephalomyocarditis virus. The expression of GBP-1 is also elevated in the blood of patients with a chronic active Epstein-Barr Virus infection. Furthermore GBP-1 and GBP-2 can potentiate the inhibitory effects of IFN-gamma on Chlamydia trachomatis growth. Finally, elevated concentrations of GBP-1 have been detected in the cerebrospinal fluid of patients with bacterial meningitis.
Entity name
Inflammation
Note
As GBP-1 is mainly expressed in endothelial cells in vivo in a context of inflammation, its effects have been extensively studied in these cells. It has been showed in endothelial cells that GBP-1 mediates the effects of inflammatory cytokines and inhibits proliferation, spreading, migration or invasion. GBP-1 is also involved in the regulation of apoptosis and senescence in endothelial cells stimulated with IFN-alpha. Evidence for an implication in cancer has been found for GBP-1 (see below).
Entity name
Colorectal carcinomas
Note
GBP-1 protein is strongly expressed in the stroma of about one third of colorectal carcinomas in association with an IFN-gamma dominated Th-1-like angiostatic immune response.
Prognosis
This expression correlates with an increased cancer-related 5-year survival.

Bibliography

Pubmed IDLast YearTitleAuthors
100872211999Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus.Anderson SL et al
39341651985Affinity purification of an interferon-induced human guanylate-binding protein and its characterization.Cheng YS et al
63059511983Interferon induction of fibroblast proteins with guanylate binding activity.Cheng YS et al
180252192007Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense.Degrandi D et al
165114972006How guanylate-binding proteins achieve assembly-stimulated processive cleavage of GTP to GMP.Ghosh A et al
128814122003The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression.Guenzi E et al
182607612008Oligonucleotide microarray analysis of gene expression profiles followed by real-time reverse-transcriptase polymerase chain reaction assay in chronic active Epstein-Barr virus infection.Ito Y et al
124145222002Guanylate-binding protein-1 expression is selectively induced by inflammatory cytokines and is an activation marker of endothelial cells during inflammatory diseases.Lubeseder-Martellato C et al
159371072005Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor.Modiano N et al
88308001996Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1.Nantais DE et al
186972002008Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy.Naschberger E et al
166896612006In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters.Olszewski MA et al
168943552006Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation.Pammer J et al
155044152004Identification of residues in the human guanylate-binding protein 1 critical for nucleotide binding and cooperative GTP hydrolysis.Praefcke GJ et al
106769682000Structure of human guanylate-binding protein 1 representing a unique class of GTP-binding proteins.Prakash B et al
109708492000Triphosphate structure of guanylate-binding protein 1 and implications for nucleotide binding and GTPase mechanism.Prakash B et al
190793322009Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-gamma and regulates barrier function through effects on apoptosis.Schnoor M et al
75125611994The interferon-induced 67-kDa guanylate-binding protein (hGBP1) is a GTPase that converts GTP to GMP.Schwemmle M et al
196527112009Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-gamma.Tietzel I et al
172664432007Unique features of different members of the human guanylate-binding protein family.Tripal P et al
161087262005The guanylate-binding proteins (GBPs): proinflammatory cytokine-induced members of the dynamin superfamily with unique GTPase activity.Vestal DJ et al
186978402008Guanylate binding protein-1 inhibits spreading and migration of endothelial cells through induction of integrin alpha4 expression.Weinländer K et al

Other Information

Locus ID:

NCBI: 2633
MIM: 600411
HGNC: 4182
Ensembl: ENSG00000117228

Variants:

dbSNP: 2633
ClinVar: 2633
TCGA: ENSG00000117228
COSMIC: GBP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000117228ENST00000370473P32455

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Interferon gamma signalingREACTOMER-HSA-877300

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
165114972006How guanylate-binding proteins achieve assembly-stimulated processive cleavage of GTP to GMP.65
115980002001The helical domain of GBP-1 mediates the inhibition of endothelial cell proliferation by inflammatory cytokines.58
230864062013Autophagy restricts Chlamydia trachomatis growth in human macrophages via IFNG-inducible guanylate binding proteins.49
128814122003The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression.47
155044152004Identification of residues in the human guanylate-binding protein 1 critical for nucleotide binding and cooperative GTP hydrolysis.36
291444522017Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence.36
211518712010Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner.35
268740792016Human GBP1 does not localize to pathogen vacuoles but restricts Toxoplasma gondii.35
186972002008Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy.32
230423002013GBP-1 acts as a tumor suppressor in colorectal cancer cells.29

Citation

Nathalie Britzen-Laurent ; Michael Stürzl

GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa)

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: http://atlasgeneticsoncology.org/gene/50147/gbp1