Perturbation of host autophagy by the Irish potato famine pathogen

Autophagy is a catabolic process involving degradation of dysfunctional cytoplasmic components to ensure cellular survival under starvation conditions. The process involves formation of double-membrane vesicles called autophagosomes and delivery of the inner constituents to lytic compartments. It can also target invading pathogens, such as intracellular bacteria, for destruction and is thus implicated in innate immune pathways [1]. In response, certain mammalian pathogens deliver effector proteins into host cells that inhibit autophagy and contribute to enabling parasitic infection [2]. Pyhtophthora infestans, the Irish potato famine pathogen, is a causative agent of late blight disease in potato and tomato crops. It delivers a plethora of modular effector proteins into plant cells to promote infection. Once inside the cell, RXLR-type effector proteins engage with host cell proteins, to manipulate host cell physiology for the benefit of the pathogen. As plants lack an adaptive immune system, this provides a robust mechanism for pathogens to circumvent host defense. PexRD54 is an intracellular RXLR-type effector protein produced by P. infestans. PexRD54 interacts with potato homologues of autophagy protein ATG8 in plant cells. We have been investigating the structural and biochemical basis of the PexRD54/ATG8 interaction in vitro. We have purified PexRD54 and ATG8 independently and in complex from E. coli. Using protein/protein interaction studies we have shown that PexRD54 binds ATG8 with sub-micromolar affinity. We have also determined the structure of PexRD54 in the presence of ATG8. This crystal structure provides key insights into how the previously reported WY-fold of oomycete RXLR-type effectors [3] can be organized in multiple repeats. The structural data also provides insights into the interaction between PexRD54 and ATG8, suggesting further experiments to understand the impact of this interaction on host cell physiology and how this benefits the pathogen.

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Chloroplasts navigate towards the pathogen interface to counteract infection by the Irish potato famine pathogen

10.1101/516443 ◽

2019 ◽

Cited By ~ 7

Author(s):

Alexia Toufexi ◽

Cian Duggan ◽

Pooja Pandey ◽

Zachary Savage ◽

María Eugenia Segretin ◽

...

Keyword(s):

Immune Activation ◽

Envelope Protein ◽

Plant Cells ◽

Irish Potato ◽

Dependent Manner ◽

Outer Envelope ◽

Pathogen Effectors ◽

Pathogen Entry ◽

Potato Famine ◽

Irish Potato Famine

AbstractChloroplasts are light harvesting organelles that arose from ancient endosymbiotic cyanobacteria. Upon immune activation, chloroplasts switch off photosynthesis, produce anti-microbial compounds, and develop tubular extensions called stromules. We report that chloroplasts navigate to the pathogen interface to counteract infection by the Irish potato famine pathogen Phytophthora infestans, physically associating with the specialised membrane that engulfs pathogen haustoria. Outer envelope protein, chloroplast unusual positioning1 (CHUP1), anchors chloroplasts to the host-pathogen interface. Stromules are induced during infection in a CHUP1-dependent manner, embracing haustoria and interconnecting chloroplasts, to form dynamic organelle clusters. Infection-triggered reprogramming of chloroplasts relies on surface immune signalling, whereas pathogen effectors subvert these immune pulses. Chloroplast are deployed focally, and coordinate to restrict pathogen entry into plant cells, a process actively countered by parasite effectors.

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The Irish potato famine pathogen subverts host vesicle trafficking to channel starvation-induced autophagy to the pathogen interface

10.1101/2020.03.20.000117 ◽

2020 ◽

Cited By ~ 2

Author(s):

Pooja Pandey ◽

Alexandre Y Leary ◽

Yasin Tümtas ◽

Zachary Savage ◽

Bayantes Dagvadorj ◽

...

Keyword(s):

Small Gtpase ◽

Effector Proteins ◽

Host Cells ◽

Irish Famine ◽

Cellular Processes ◽

Autophagy Pathway ◽

Basal Immunity ◽

Endomembrane Trafficking ◽

Potato Famine ◽

Irish Potato Famine

SummaryEukaryotic cells deploy autophagy to eliminate invading microbes. In turn, pathogens have evolved effector proteins to counteract antimicrobial autophagy. How and why adapted pathogens co-opt autophagy for their own benefit is poorly understood. The Irish famine pathogen Phythophthora infestans secretes the effector protein PexRD54 that selectively activates an unknown plant autophagy pathway, while antagonizing antimicrobial autophagy. Here we show that PexRD54 induces autophagosome formation by bridging small GTPase Rab8a-decorated vesicles with autophagic compartments labelled by the core autophagy protein ATG8CL. Rab8a is required for pathogen-triggered and starvation-induced but not antimicrobial autophagy, revealing that specific trafficking pathways underpin selective autophagy. We discovered that Rab8a contributes to basal immunity against P. infestans, but PexRD54 diverts a sub-population of Rab8a vesicles to lipid droplets that associate with autophagosomes. These are then diverted towards pathogen feeding structures that are accommodated within the host cells. We propose that PexRD54 mimics starvation-induced autophagy by channeling host endomembrane trafficking towards the pathogen interface possibly to acquire nutrients. This work reveals that effectors can interconnect independent host compartments to stimulate complex cellular processes that benefit the pathogen.Graphical abstract

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Host autophagosomes are diverted to a plant-pathogen interface

10.1101/102996 ◽

2017 ◽

Cited By ~ 3

Author(s):

Yasin F Dagdas ◽

Pooja Pandey ◽

Nattapong Sanguankiattichai ◽

Yasin Tumtas ◽

Khaoula Belhaj ◽

...

Keyword(s):

Phytophthora Infestans ◽

Plant Pathogen ◽

Plant Pathogens ◽

Irish Potato ◽

Host Protein ◽

Host Cells ◽

Autophagosome Formation ◽

Selective Autophagy ◽

Potato Famine ◽

Irish Potato Famine

AbstractFilamentous plant pathogens and symbionts invade their host cells but remain enveloped by host-derived membranes. The mechanisms underlying the biogenesis and functions of these host-microbe interfaces are poorly understood. Recently, we showed that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host protein ATG8CL to stimulate autophagosome formation and deplete the selective autophagy receptor Joka2 from ATG8CL complexes. Here, we show that during P. infestans infection, ATG8CL autophagosomes are diverted to the pathogen interface. Our findings are consistent with the view that the pathogen coopts host selective autophagy for its own benefit.

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Correction: The Irish Potato Famine Pathogen Phytophthora infestans Translocates the CRN8 Kinase into Host Plant Cells

PLoS Pathogens ◽

10.1371/journal.ppat.1004753 ◽

2015 ◽

Vol 11 (3) ◽

pp. e1004753

Author(s):

Keyword(s):

Phytophthora Infestans ◽

Host Plant ◽

Plant Cells ◽

Irish Potato ◽

Potato Famine ◽

Irish Potato Famine

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The Irish Potato Famine Pathogen Phytophthora infestans Translocates the CRN8 Kinase into Host Plant Cells

PLoS Pathogens ◽

10.1371/journal.ppat.1002875 ◽

2012 ◽

Vol 8 (8) ◽

pp. e1002875 ◽

Cited By ~ 48

Author(s):

Mireille van Damme ◽

Tolga O. Bozkurt ◽

Cahid Cakir ◽

Sebastian Schornack ◽

Jan Sklenar ◽

...

Keyword(s):

Phytophthora Infestans ◽

Host Plant ◽

Plant Cells ◽

Irish Potato ◽

Potato Famine ◽

Irish Potato Famine

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The Modes of Action of MARTX Toxin Effector Domains

Toxins ◽

10.3390/toxins10120507 ◽

2018 ◽

Vol 10 (12) ◽

pp. 507 ◽

Cited By ~ 9

Author(s):

Byoung Kim

Keyword(s):

Host Cell ◽

Structural Features ◽

Effector Proteins ◽

Host Cells ◽

Cell Physiology ◽

Cytotoxic Activities ◽

Human Pathogens ◽

Secretion Systems ◽

Gram Negative ◽

Effector Domains

Many Gram-negative bacterial pathogens directly deliver numerous effector proteins from the bacterium to the host cell, thereby altering the target cell physiology. The already well-characterized effector delivery systems are type III, type IV, and type VI secretion systems. Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are another effector delivery platform employed by some genera of Gram-negative bacteria. These single polypeptide exotoxins possess up to five effector domains in a modular fashion in their central regions. Upon binding to the host cell plasma membrane, MARTX toxins form a pore using amino- and carboxyl-terminal repeat-containing arms and translocate the effector domains into the cells. Consequently, MARTX toxins affect the integrity of the host cells and often induce cell death. Thus, they have been characterized as crucial virulence factors of certain human pathogens. This review covers how each of the MARTX toxin effector domains exhibits cytopathic and/or cytotoxic activities in cells, with their structural features revealed recently. In addition, future directions for the comprehensive understanding of MARTX toxin-mediated pathogenesis are discussed.

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MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to Toxoplasma , Including Counteracting MYR1-Independent Effects

mBio ◽

10.1128/mbio.02401-17 ◽

2018 ◽

Vol 9 (2) ◽

Cited By ~ 27

Author(s):

Adit Naor ◽

Michael W. Panas ◽

Nicole Marino ◽

Michael J. Coffey ◽

Christopher J. Tonkin ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Host Cell ◽

Expression Profiles ◽

Parasitophorous Vacuole ◽

Effector Proteins ◽

Gene Set Enrichment Analysis ◽

Host Cells ◽

Content Type ◽

Cell Functions ◽

The Impact

ABSTRACT The obligate intracellular parasite Toxoplasma gondii controls its host cell from within the parasitophorous vacuole (PV) by using a number of diverse effector proteins, a subset of which require the aspartyl protease 5 enzyme (ASP5) and/or the recently discovered MYR1 protein to cross the PV membrane. To examine the impact these effectors have in the context of the entirety of the host response to Toxoplasma , we used RNA-Seq to analyze the transcriptome expression profiles of human foreskin fibroblasts infected with wild-type RH (RH-WT), RHΔ myr1 , and RHΔ asp5 tachyzoites. Interestingly, the majority of the differentially regulated genes responding to Toxoplasma infection are MYR1 dependent. A subset of MYR1 responses were ASP5 independent, and MYR1 function did not require ASP5 cleavage, suggesting the export of some effectors requires only MYR1. Gene set enrichment analysis of MYR1-dependent host responses suggests an upregulation of E2F transcription factors and the cell cycle and a downregulation related to interferon signaling, among numerous others. Most surprisingly, “hidden” responses arising in RHΔ myr1 - but not RH-WT-infected host cells indicate counterbalancing actions of MYR1-dependent and -independent activities. The host genes and gene sets revealed here to be MYR1 dependent provide new insight into the parasite’s ability to co-opt host cell functions. IMPORTANCE Toxoplasma gondii is unique in its ability to successfully invade and replicate in a broad range of host species and cells within those hosts. The complex interplay of effector proteins exported by Toxoplasma is key to its success in co-opting the host cell to create a favorable replicative niche. Here we show that a majority of the transcriptomic effects in tachyzoite-infected cells depend on the activity of a novel translocation system involving MYR1 and that the effectors delivered by this system are part of an intricate interplay of activators and suppressors. Removal of all MYR1-dependent effectors reveals previously unknown activities that are masked or hidden by the action of these proteins.

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