Phevamine A, a small molecule that suppresses plant immune responses

Bacterial plant pathogens cause significant crop damage worldwide. They invade plant cells by producing a variety of virulence factors, including small-molecule toxins and phytohormone mimics. Virulence of the model pathogen Pseudomonas syringae pv. tomato DC3000 (Pto) is regulated in part by the sigma factor HrpL. Our study of the HrpL regulon identified an uncharacterized, three-gene operon in Pto that is controlled by HrpL and related to the Erwinia hrp-associated systemic virulence (hsv) operon. Here, we demonstrate that the hsv operon contributes to the virulence of Pto on Arabidopsis thaliana and suppresses bacteria-induced immune responses. We show that the hsv-encoded enzymes in Pto synthesize a small molecule, phevamine A. This molecule consists of l-phenylalanine, l-valine, and a modified spermidine, and is different from known small molecules produced by phytopathogens. We show that phevamine A suppresses a potentiation effect of spermidine and l-arginine on the reactive oxygen species burst generated upon recognition of bacterial flagellin. The hsv operon is found in the genomes of divergent bacterial genera, including ∼37% of P. syringae genomes, suggesting that phevamine A is a widely distributed virulence factor in phytopathogens. Our work identifies a small-molecule virulence factor and reveals a mechanism by which bacterial pathogens overcome plant defense. This work highlights the power of omics approaches in identifying important small molecules in bacteria–host interactions.

Download Full-text

Structure of the HopA1(21-102)-ShcA Chaperone-Effector Complex of Pseudomonas syringae Reveals Conservation of a Virulence Factor Binding Motif from Animal to Plant Pathogens

Journal of Bacteriology ◽

10.1128/jb.01621-12 ◽

2012 ◽

Vol 195 (4) ◽

pp. 658-664 ◽

Cited By ~ 16

Author(s):

R. Janjusevic ◽

C. M. Quezada ◽

J. Small ◽

C. E. Stebbins

Keyword(s):

Pseudomonas Syringae ◽

Virulence Factor ◽

Plant Pathogens ◽

Binding Motif ◽

Factor Binding

Download Full-text

A Breach in Plant Defences: Pseudomonas syringae pv. actinidiae Targets Ethylene Signalling to Overcome Actinidia chinensis Pathogen Responses

International Journal of Molecular Sciences ◽

10.3390/ijms22094375 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4375

Author(s):

Antonio Cellini ◽

Irene Donati ◽

Brian Farneti ◽

Iuliia Khomenko ◽

Giampaolo Buriani ◽

...

Keyword(s):

Immune Responses ◽

Pseudomonas Syringae ◽

Ethylene Production ◽

Plant Pathogens ◽

In Planta ◽

Virulence Trait ◽

Exogenous Ethylene ◽

Ethylene Signalling ◽

Highly Virulent

Ethylene interacts with other plant hormones to modulate many aspects of plant metabolism, including defence and stomata regulation. Therefore, its manipulation may allow plant pathogens to overcome the host’s immune responses. This work investigates the role of ethylene as a virulence factor for Pseudomonas syringae pv. actinidiae (Psa), the aetiological agent of the bacterial canker of kiwifruit. The pandemic, highly virulent biovar of this pathogen produces ethylene, whereas the biovars isolated in Japan and Korea do not. Ethylene production is modulated in planta by light/dark cycle. Exogenous ethylene application stimulates bacterial virulence, and restricts or increases host colonisation if performed before or after inoculation, respectively. The deletion of a gene, unrelated to known bacterial biosynthetic pathways and putatively encoding for an oxidoreductase, abolishes ethylene production and reduces the pathogen growth rate in planta. Ethylene production by Psa may be a recently and independently evolved virulence trait in the arms race against the host. Plant- and pathogen-derived ethylene may concur in the activation/suppression of immune responses, in the chemotaxis toward a suitable entry point, or in the endophytic colonisation.

Download Full-text

Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

Cancers ◽

10.3390/cancers13143386 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3386

Author(s):

Bart Spiesschaert ◽

Katharina Angerer ◽

John Park ◽

Guido Wollmann

Keyword(s):

Immune Response ◽

Immune Responses ◽

Tumor Cells ◽

Small Molecule ◽

Antiviral Immunity ◽

Oncolytic Viruses ◽

Antitumor Immune Response ◽

Antiviral Responses ◽

Small Molecule Therapeutics ◽

Immunosuppressive Factors

The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

Download Full-text

An efficient direct screening system for microorganisms that activate plant immune responses based on plant–microbe interactions using cultured plant cells

Scientific Reports ◽

10.1038/s41598-021-86560-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mari Kurokawa ◽

Masataka Nakano ◽

Nobutaka Kitahata ◽

Kazuyuki Kuchitsu ◽

Toshiki Furuya

Keyword(s):

Immune Responses ◽

Plant Defense ◽

Pseudomonas Syringae ◽

Large Scale ◽

Plant Cells ◽

Defense Responses ◽

Root Tip ◽

General Strategy ◽

Plant Defense Responses ◽

Microbe Interactions

AbstractMicroorganisms that activate plant immune responses have attracted considerable attention as potential biocontrol agents in agriculture because they could reduce agrochemical use. However, conventional methods to screen for such microorganisms using whole plants and pathogens are generally laborious and time consuming. Here, we describe a general strategy using cultured plant cells to identify microorganisms that activate plant defense responses based on plant–microbe interactions. Microbial cells were incubated with tobacco BY-2 cells, followed by treatment with cryptogein, a proteinaceous elicitor of tobacco immune responses secreted by an oomycete. Cryptogein-induced production of reactive oxygen species (ROS) in BY-2 cells served as a marker to evaluate the potential of microorganisms to activate plant defense responses. Twenty-nine bacterial strains isolated from the interior of Brassica rapa var. perviridis plants were screened, and 8 strains that enhanced cryptogein-induced ROS production in BY-2 cells were selected. Following application of these strains to the root tip of Arabidopsis seedlings, two strains, Delftia sp. BR1R-2 and Arthrobacter sp. BR2S-6, were found to induce whole-plant resistance to bacterial pathogens (Pseudomonas syringae pv. tomato DC3000 and Pectobacterium carotovora subsp. carotovora NBRC 14082). Pathogen-induced expression of plant defense-related genes (PR-1, PR-5, and PDF1.2) was enhanced by the pretreatment with strain BR1R-2. This cell–cell interaction-based platform is readily applicable to large-scale screening for microorganisms that enhance plant defense responses under various environmental conditions.

Download Full-text

Small-Molecule Targeted Aβ42 Aggregate Degradation: Negatively Charged Small Molecules Are More Promising than the Neutral Ones

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.1c00047 ◽

2021 ◽

Author(s):

Jinfei Mei ◽

Huijuan Yang ◽

Bo Sun ◽

Chengqiang Liu ◽

Hongqi Ai

Keyword(s):

Small Molecules ◽

Small Molecule

Download Full-text

STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

Neuro-Oncology ◽

10.1093/neuonc/noaa215.837 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Stephen Skirboll ◽

Natasha Lucki ◽

Genaro Villa ◽

Naja Vergani ◽

Michael Bollong ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Small Molecules ◽

Small Molecule ◽

Large Scale ◽

Critical Role ◽

Tumor Formation ◽

Cell Type ◽

Caspase 1 ◽

Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

Download Full-text

337 Metabolic Foundations of Microbiota-Host Interactions

Journal of Animal Science ◽

10.1093/jas/skaa278.126 ◽

2020 ◽

Vol 98 (Supplement_4) ◽

pp. 69-69

Author(s):

Dylan Dodd

Keyword(s):

Gastrointestinal Tract ◽

Gut Microbiota ◽

Small Molecules ◽

Recent Work ◽

Mechanistic Studies ◽

Therapeutic Approaches ◽

Dense Population ◽

Metabolic Potential ◽

Host Interactions ◽

New Therapeutic Approaches

Abstract The gastrointestinal tract of mammals is home to a dense population of microbes which influence host physiology and health. One of the most concrete ways that the gut microbiota impacts host biology is through the production of hundreds of chemically diverse small molecules. These molecules are absorbed into the bloodstream, where they reach concentrations similar to those achieved by pharmaceuticals and bind host receptors leading to changes in cellular and organ physiology. Here I will summarize recent work from our group and others that show how microbially sourced metabolites alter health and physiology of the host. I will also discuss how mechanistic studies of small molecules from the microbiota are enabling new therapeutic approaches to harness the metabolic potential of the gut microbiota.

Download Full-text

BAK1 Is Not a Target of the Pseudomonas syringae Effector AvrPto

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-04-10-0096 ◽

2011 ◽

Vol 24 (1) ◽

pp. 100-107 ◽

Cited By ~ 49

Author(s):

Tingting Xiang ◽

Na Zong ◽

Jie Zhang ◽

Jinfeng Chen ◽

Mingsheng Chen ◽

...

Keyword(s):

Cell Surface ◽

Immune Responses ◽

Pseudomonas Syringae ◽

Plant Cell ◽

Crucial Role ◽

Pathogenic Bacteria ◽

Effector Proteins ◽

Receptor Like Kinase ◽

Receptor Kinases ◽

New Evidence

Plant cell surface-localized receptor kinases such as FLS2, EFR, and CERK1 play a crucial role in detecting invading pathogenic bacteria. Upon stimulation by bacterium-derived ligands, FLS2 and EFR interact with BAK1, a receptor-like kinase, to activate immune responses. A number of Pseudomonas syringae effector proteins are known to block immune responses mediated by these receptors. Previous reports suggested that both FLS2 and BAK1 could be targeted by the P. syringae effector AvrPto to inhibit plant defenses. Here, we provide new evidence further supporting that FLS2 but not BAK1 is targeted by AvrPto in plants. The AvrPto-FLS2 interaction prevented the phosphorylation of BIK1, a downstream component of the FLS2 pathway.

Download Full-text