scholarly journals Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems

2017 ◽  
Vol 114 (9) ◽  
pp. E1698-E1706 ◽  
Author(s):  
Eric M. Feeley ◽  
Danielle M. Pilla-Moffett ◽  
Erin E. Zwack ◽  
Anthony S. Piro ◽  
Ryan Finethy ◽  
...  
Keyword(s):  
Host Defense ◽  
Binding Proteins ◽  
Host Cells ◽  
Carbohydrate Binding ◽  
Bacterial Protein ◽  
Secretion Systems ◽  
Defense Proteins ◽  
Galectin 3 ◽  
Protein Secretion Systems ◽  
Bacterial Secretion

Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as “patterns of pathogenesis” associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersinia-containing vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3–deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3–dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.

scholarly journals Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Erin E. Zwack ◽  
Eric M. Feeley ◽  
Amanda R. Burton ◽  
Baofeng Hu ◽  
Masahiro Yamamoto ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Membrane Damage ◽  
Effector Proteins ◽  
Host Cells ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Secretion Systems ◽  
Content Type ◽  
Endosomal Membrane ◽  
Galectin 3

ABSTRACT Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by nucleotide binding domain and leucine-rich repeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 (Gbp Chr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

scholarly journals Guanylate Binding Proteins Restrict Leishmania donovani Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Arun Kumar Haldar ◽  
Utsav Nigam ◽  
Masahiro Yamamoto ◽  
Jörn Coers ◽  
Neena Goyal
Keyword(s):  
Host Defense ◽  
Leishmania Donovani ◽  
Binding Proteins ◽  
Critical Role ◽  
Intrinsic Property ◽  
Epithelial Cell Line ◽  
Cell Type ◽  
Phagocytic Cells ◽  
Defense Proteins ◽  
Content Type

ABSTRACT Interferon (IFN)-inducible guanylate binding proteins (GBPs) play important roles in host defense against many intracellular pathogens that reside within pathogen-containing vacuoles (PVs). For instance, members of the GBP family translocate to PVs occupied by the protozoan pathogen Toxoplasma and facilitate PV disruption and lytic parasite killing. While the GBP defense program targeting Toxoplasma has been studied in some detail, the role of GBPs in host defense to other protozoan pathogens is poorly characterized. Here, we report a critical role for both mouse and human GBPs in the cell-autonomous immune response against the vector-borne parasite Leishmania donovani. Although L. donovani can infect both phagocytic and nonphagocytic cells, it predominantly replicates inside professional phagocytes. The underlying basis for this cell type tropism is unclear. Here, we demonstrate that GBPs restrict growth of L. donovani in both mouse and human nonphagocytic cells. GBP-mediated restriction of L. donovani replication occurs via a noncanonical pathway that operates independent of detectable translocation of GBPs to L. donovan-containing vacuoles (LCVs). Instead of promoting the lytic destruction of PVs, as reported for GBP-mediated killing of Toxoplasma in phagocytic cells, GBPs facilitate the delivery of L. donovani into autolysosomal-marker-positive compartments in mouse embryonic fibroblasts as well as the human epithelial cell line A549. Together our results show that GBPs control a novel cell-autonomous host defense program, which renders nonphagocytic cells nonpermissible for efficient Leishmania replication. IMPORTANCE The obligate intracellular parasite Leishmania causes the disease leishmaniasis, which is transmitted to mammalian hosts, including humans, via the sandfly vector. Following the bite-induced breach of the skin barrier, Leishmania is known to live and replicate predominantly inside professional phagocytes. Although Leishmania is also able to infect nonphagocytic cells, nonphagocytic cells support limited parasitic replication for unknown reasons. In this study, we show that nonphagocytic cells possess an intrinsic property to restrict Leishmania growth. Our study defines a novel role for a family of host defense proteins, the guanylate binding proteins (GBPs), in antileishmanial immunity. Mechanistically, our data indicate that GBPs facilitate the delivery of Leishmania into antimicrobial autolysosomes, thereby enhancing parasite clearance in nonphagocytic cells. We propose that this GBP-dependent host defense program makes nonphagocytic cells an inhospitable host cell type for Leishmania growth.

scholarly journals Export von Gefahrgut: Helicobacter pylori und sein CagA-Protein

BIOspektrum ◽  
2020 ◽  
Vol 26 (6) ◽  
pp. 597-599
Author(s):  
Clara Lettl ◽  
Wolfgang Fischer
Keyword(s):  
Helicobacter Pylori ◽  
Pathogenic Bacteria ◽  
Type Iv Secretion ◽  
Host Cells ◽  
Bacterial Protein ◽  
Secretion Systems ◽  
Unusual Structure ◽  
Type Iv ◽  
Single Protein ◽  
Protein Transporters

Abstract Pathogenic bacteria often utilize type IV secretion systems to interact with host cells and to modify their microenvironment in a favourable way. The human pathogen Helicobacter pylori produces such a system to inject only a single protein, CagA, into gastric cells, but this injection represents a major risk factor for gastric cancer development. Here, we discuss the unusual structure of the Cag secretion nanomachine and other features that make it unique among bacterial protein transporters.

scholarly journals Detection of cytosolicShigella flexnerivia a C-terminal triple-arginine motif of GBP1 inhibits actin-based motility

2017 ◽  
Author(s):  
Anthony S. Piro ◽  
Dulcemaria Hernandez ◽  
Sarah Luoma ◽  
Eric. M. Feeley ◽  
Ryan Finethy ◽  
...  
Keyword(s):  
Host Cell ◽  
Host Defense ◽  
Actin Polymerization ◽  
Bacterial Pathogens ◽  
Bacterial Species ◽  
Host Cells ◽  
Host Recognition ◽  
Gram Negative Bacteria ◽  
Defense Proteins ◽  
Gram Negative

AbstractDynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFNγ)-inducible host defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique amongst the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria,Burkholderia thailandensisandShigella flexneri.Rough lipopolysaccharide (LPS) mutants ofS. flexnerico-localize with GBP1 less frequently than wildtypeS. flexneri, suggesting that host recognition of O-antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C-terminus, promotes the co-recruitment of four additional GBP paralogs (GBP2, GBP3, GBP4 and GBP6). GBP1-decoratedShigellareplicate but fail to form actin tails leading to their intracellular aggregation. Consequentially, wildtype but not the triple-arginine GBP1 mutant restrictsS. flexnericell-to-cell spread. Furthermore, human-adaptedS. flexneri,through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillusB. thailandensis. These studies reveal that human GBP1 uniquely functions as an intracellular ‘glue trap’ inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human defense programS. flexnerihas evolved an effective counter-defense to restrict GBP1 recruitment.ImportanceSeveral pathogenic bacterial species evolved to invade, reside and replicate inside the cytosol of their host cells. One adaptation common to most cytosolic bacterial pathogens is the ability to co-opt the host’s actin polymerization machinery, in order to generate force for intracellular movement. This actin-based motility enables Gram-negative bacteria such asShigellato propel themselves into neighboring cells thereby spreading from host cell to host cell without exiting the intracellular environment. Here, we show that the human protein GBP1 acts as a cytosolic ‘glue trap’ capturing cytosolic Gram-negative bacteria through a unique protein motif and preventing disseminated infections in cell culture models. To escape from this GBP1-mediated host defense,Shigellaemploys a virulence factor that prevents or dislodges the association of GBP1 with cytosolic bacteria. Thus, therapeutic strategies to restore GBP1 binding toShigellamay lead to novel treatment options for shigellosis in the future.

Bacterial Protein Secretion Systems

2013 ◽  
pp. 183-213 ◽  
Author(s):  
I Jiménez-Guerrero ◽  
M Cubo ◽  
F Pérez-Montaño ◽  
F López-Baena ◽  
B Guash-Vidal ◽  
...  
Keyword(s):  
Protein Secretion ◽  
Bacterial Protein ◽  
Secretion Systems ◽  
Protein Secretion Systems

scholarly journals Structural perspectives on bacterial secretion machines

2014 ◽  
Vol 70 (a1) ◽  
pp. C575-C575
Author(s):  
Susan Lea
Keyword(s):  
Biological Effects ◽  
Host Cells ◽  
Structural Studies ◽  
Secretion Systems ◽  
System A ◽  
Type Three Secretion System ◽  
Wide Range ◽  
Tat System ◽  
Structural Methods ◽  
Bacterial Secretion

For any cellular secretion mechanisms the key questions that need to be understood center on the processes that ensure how secretion is achieved without disruption of the membrane barrier, how the process is energized and how substrates are selected. We are pursuing structural studies of two very different bacterial secretion systems that take almost opposite approaches to this but where structures are beginning to give insight into mechanism. Recent work will be presented contrasting the Twin Arginine Transport (or Tat) system, a relatively simple 2 or 3 component system that manages to transport a wide range of fully-folded protein substrates, of very different size, shape and charge without promoting leakage from the cell with the Type Three Secretion System (or T3SS) a protein nano-machine constructed of more than 15 proteins that secretes fully unfolded substrates directly into a pathogen's host cells. Comparing the two systems yet again demonstrates how very different mechanisms and architectures can be used to achieve much more similar biological effects. The difficulties presented for structural studies of by these systems will also be highlighted as will the use of mixed structural methods to extend our understanding.

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