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Review
. 2019 Mar 4;216(3):482-500.
doi: 10.1084/jem.20182031. Epub 2019 Feb 12.

Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

Kyle Tretina  1   2   3 , Eui-Soon Park  1   2   3 , Agnieszka Maminska  1   2   3 , John D MacMicking  4   2   3
Affiliations
Review

Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

Kyle Tretina et al. J Exp Med. .

Abstract

Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings. A better understanding of the basic biology of these IFN-induced GTPases could thus benefit clinical approaches to a wide spectrum of important human diseases.

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Figures

Figure 1.
Figure 1.
GBPs are ancient and widely distributed in eukaryotes. A comprehensive in silico scan of 91 taxa from Shenoy et al. (2012) plus newer deposits yielded this circular dendrogram with emphasis on human GBP-related orthologues. Sequences were aligned with the E-INS-i algorithm (MAFFT v7) and taxa with incomplete data removed via MaxAlign version 1.1. Right: The phylogenetic tree was constructed using a modified version of the unweighted pair group method with arithmetic mean clustering as implemented by MAFFT. Left: A TimeTree diagram (http://www.timetree.org) depicts the ancient origin of GBPs in lineages leading to Homo sapiens.
Figure 2.
Figure 2.
Composition of GBP families among closely related primates. Overlapping genomic contigs for primate GBP cluster assembly reveal differences for GBP5 in selected Great Apes versus Old World monkeys. Alignment of the GBP clusters were extracted from the Ensembl database with mRNA transcripts validated for the encoded genes in multiple repositories. Blue regions depict contig regions. Red bars cover individual GBP loci.
Figure 3.
Figure 3.
Human GBP domain structure and response to IFNs. (A) Top: Some GBPs share orthology with core inflammasome components as revealed by domain accretion in other taxa. Zebrafish GBP3 and GBP4 harbor GTPase (G) and C-terminal helical domains (H) fused to CARDs (C). The latter are orthologous to CARD fusions in human NLRP1, ASC, and caspase-4. Bottom: Similar CARD domain surface structures from zebrafish GBP3 (PDB 4IRL) and human NLRP1 (4IFP; https://www.ebi.ac.uk/pdbe). (B) Crystal structure of human GBP1 bound to the GTP analogue GMPPNP (RCSB Protein Data Bank accession no. 1F5N) reveals a bidomain architecture: N-terminal GTPase and C-terminal helical domains. Two-step GTP hydrolysis shown above. (C) GBP mRNA expression levels robustly induced with IFNs from multiple microarray and RNA sequencing studies deposited in the Interferome database and Bolen et al. (2014). (D) Position of IFN-dependent binding sites for transactivation validated in CHIP-seq ENCODE data from human cells induced with IFN-α or -β (IRF1), IFN-γ (STAT1), or untreated (STAT3, IRF4), or treated with OHTAM/ethanol (STAT3; https://genome.ucsc.edu). CP, cysteine protease domains; F, function to find; P, pyrin; N, NACHT domain; LRR, leucine-rich repeat; CHIP-seq, chromatin immunoprecipitation sequencing.
Figure 4.
Figure 4.
Diverse GBP expression under homeostatic and disease conditions. Left: Homeostatic expression of different GBP proteins varies between human tissues. Heat maps generated from data deposited in the Human Protein Atlas consortium (https://www.proteinatlas.org/). mRNA data are shown for GBP7 due to a lack of antibody validation for this GBP. Right: GBP protein expression in human tissues during different disease states from the Human Protein Atlas consortium. Scale values shown in each case below heat maps. N.D., not detectable.
Figure 5.
Figure 5.
Antimicrobial activities of GBPs. (A) Targeting of human GBP1 to cytosolic S. typhimurium via live epifluorescent imaging in IFN-γ–activated human HeLa epithelium. Bar, 3 µm. Courtesy of A. Maminska. (B) Specific cell-autonomous responses of GBPs to different pathogen classes and the downstream consequences of their antimicrobial actions in humans (h), mice (m), and zebrafish (z). (C) Involvement of different GBPs from humans, mice, and zebrafish in canonical and noncanonical inflammasome activation elicited by microbial ligands as input signals. Cytokine and prostaglandin secretion plus pyroptosis are identified outputs. Inflammasome cryoelectron tomography structure (3JBL) from https://www.ebi.ac.uk/pdbe. MDP, muramyl dipeptide.
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