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

Tretina, Kyle; Park, Eui‐Soon; Mamińska, Agnieszka; MacMicking, John D.

doi:10.1084/jem.20182031

Cited by 190 publications

(188 citation statements)

References 173 publications

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“…GTP binding and hydrolysis promotes the dimerization, oligomerization, and polymerization of GBPs as well as recruitment of additional GBP family members (6) . Oligomerization of GBPs on pathogen-containing membrane-bound compartments prompts an array of antimicrobial activities including the production of radical oxygen species by co-recruited oxidases, the fusion of these compartments with degradative lysosomes, their encapsulation within autophagosome-like structures, or the lytic disintegration of microbe-containing compartments (7) . Some GBPs also possess the ability to target microbes that reside inside the host cell cytosol.…”

Section: Introductionmentioning

confidence: 99%

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Köhler

Kutsch

Piro

et al. 2019

Preprint

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Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri . By swapping this membrane-binding motif between primate GBP orthologs, we find that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World monkeys. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense.

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Section: Introductionmentioning

confidence: 99%

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Köhler

Kutsch

Piro

et al. 2019

Preprint

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“…These innate mechanisms allow the cell to rapidly detect, target and destroy invading pathogens, preventing the spread of an infection. The immune pathways controlling innate immunity arose early in the evolution of the eukaryota, providing ample time for the selection of pathogens that express mechanisms to bypass cell-autonomous immunity (2). This long-term arms race has produced a myriad of interactions between immune effectors and pathogen countermeasures that determine the outcome of an infection.…”

Section: Introductionmentioning

confidence: 99%

“…IFNg-induced oxygen and nitrogen radical generation limits Mtb replication in macrophages ex vivo, but appear to serve a limited antimicrobial role in the intact animal (14)(15)(16). Instead, a subset of IFNg-inducible cell-intrinsic immune mechanisms, known as Guanylate binding proteins (GBPs), target and disrupt the intracellular niche required for a number of pathogens to grow (2,(17)(18)(19)(20)(21). Macrophages lacking GBPs 1, 6,7 or 10 fail to control the growth of M. bovis BCG, an attenuated vaccine strain that is closely related to Mtb (22).…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosisevasion of Guanylate Binding Protein-mediated host defense in mice requires the ESX1 secretion system

Olive

Smith

Baer

et al. 2020

Preprint

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Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb, it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict Mycobacterium bovis BCG yet their role during Mtb infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While M. bovis BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of Mtb replication or the associated host response to infection. The differential effects of GBPs during Mtb versus M. bovis BCG infection is at least partially explained by the absence of the ESX1 secretion system from M. bovis BCG, since Mtb mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and Mycobacteria reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity.

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“…Among 18 these proteins are the guanylate binding proteins (GBPs), which belong to the 19 dynamin-related protein family, even though the GTPase domain is the only conserved 20 sequence. They have various functions in the resistance against intracellular pathogens 21 via GTP binding and hydrolysis [1][2][3][4][5]. Generally, an infection is followed by the Fig 1. Conformation of the nucleotide-bound hGBP1 crystal structure (PDB 1F5N).…”

Section: Introductionmentioning

confidence: 99%

Large-scale, dynamin-like motions of the human guanylate binding protein 1 revealed by multi-resolution simulations

Barz

Loschwitz

Strodel

2019

Preprint

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Guanylate binding proteins (GBPs) belong to the dynamin-related superfamily and exhibit various functions in the fight against infections. The functions of the human guanylate binding protein 1 (hGBP1) are tightly coupled to GTP hydrolysis and dimerization. Despite known crystal structures of the hGBP1 monomer and GTPase domain dimer, little is known about the dynamics of hGBP1. To gain a mechanistic understanding of hGBP1, we performed sub-millisecond multi-resolution molecular dynamics simulations of both the hGBP1 monomer and dimer. We found that hGBP1 is a highly flexible protein that undergoes a hinge motion similar to the movements observed for other dynamin-like proteins. Another large-scale motion was observed for the C-terminal helix α13, providing a molecular view for the α13-α13 distances previously reported for the hGBP1 dimer. Most of the loops of the GTPase domain were found to be flexible, disclosing why GTP binding is needed for hGBP1 dimerization to occur.

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

Cited by 190 publications

References 173 publications

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Mycobacterium tuberculosisevasion of Guanylate Binding Protein-mediated host defense in mice requires the ESX1 secretion system

Large-scale, dynamin-like motions of the human guanylate binding protein 1 revealed by multi-resolution simulations

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