TOB is an effector of the hippocampus-mediated acute stress response
Mohieldin YoussefHiro Taiyo HamadaSuk‐King LaiYuji KiyamaMohamed El‐TabbalHiroshi KiyonariKohei NakanoBernd KühnTadashi Yamamoto
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Stress affects behavior and involves critical dynamic changes at multiple levels ranging from molecular pathways to neural circuits and behavior. Abnormalities at any of these levels lead to decreased stress resilience and pathological behavior. However, temporal modulation of molecular pathways underlying stress response remains poorly understood. Transducer of ErbB2.1, known as TOB, is involved in different physiological functions, including cellular stress and immediate response to stimulation. In this study, we investigated the role of TOB in psychological stress machinery at molecular, neural circuit, and behavioral levels. Interestingly, TOB protein levels increased after mice were exposed to acute stress. At the neural circuit level, functional magnetic resonance imaging (fMRI) suggested that intra-hippocampal and hippocampal-prefrontal connectivity were dysregulated in Tob knockout (Tob-KO) mice. Electrophysiological recordings in hippocampal slices showed increased postsynaptic AMPAR-mediated neurotransmission, accompanied by decreased GABA neurotransmission and subsequently altered Excitatory/Inhibitory balance after Tob deletion. At the behavioral level, Tob-KO mice show abnormal, hippocampus-dependent, contextual fear conditioning and extinction, and depression-like behaviors. On the other hand, increased anxiety observed in Tob-KO mice is hippocampus-independent. At the molecular level, we observed changes in factors involved in stress response like decreased stress-induced LCN2 expression and ERK phosphorylation, as well as increased MKP-1 expression. This study introduces TOB as an important modulator in the hippocampal stress signaling machinery. In summary, we reveal a molecular pathway and neural circuit mechanism by which Tob deletion contributes to expression of pathological stress-related behavior.Abstract Pathogens deliver complex arsenals of translocated effector proteins to host cells during infection, but the extent to which these proteins are regulated once inside the eukaryotic cell remains poorly defined. Among all bacterial pathogens, Legionella pneumophila maintains the largest known set of translocated substrates, delivering over 300 proteins to the host cell via its Type IVB , Icm/Dot translocation system. Backed by a few notable examples of effector–effector regulation in L. pneumophila , we sought to define the extent of this phenomenon through a systematic analysis of effector–effector functional interaction. We used Saccharomyces cerevisiae , an established proxy for the eukaryotic host, to query > 108,000 pairwise genetic interactions between two compatible expression libraries of ~330 L. pneumophila‐ translocated substrates. While capturing all known examples of effector–effector suppression, we identify fourteen novel translocated substrates that suppress the activity of other bacterial effectors and one pair with synergistic activities. In at least nine instances, this regulation is direct—a hallmark of an emerging class of proteins called metaeffectors, or “effectors of effectors”. Through detailed structural and functional analysis, we show that metaeffector activity derives from a diverse range of mechanisms, shapes evolution, and can be used to reveal important aspects of each cognate effector's function. Metaeffectors, along with other, indirect, forms of effector–effector modulation, may be a common feature of many intracellular pathogens—with unrealized potential to inform our understanding of how pathogens regulate their interactions with the host cell.
Legionella
Intracellular parasite
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Horticultural crops suffer from bacterial, fungal, and oomycete pathogens. Effectors are one of the main weapons deployed by those pathogens, especially in the early stages of infection. Pathogens secrete effectors with diverse functions to avoid recognition by plants, inhibit or manipulate plant immunity, and induce programmed cell death. Most identified effectors are proteinaceous, such as the well-studied type-III secretion system effectors (T3SEs) in bacteria, RXLR and CRN (crinkling and necrosis) motif effectors in oomycetes, and LysM (lysin motifs) domain effectors in fungi. In addition, some non-proteinaceous effectors such as toxins and sRNA also play crucial roles in infection. To cope with effectors, plants have evolved specific mechanisms to recognize them and activate effector-triggered immunity (ETI). This review summarizes the functions and mechanisms of action of typical proteinaceous and non-proteinaceous effectors secreted by important horticultural crop pathogens. The defense responses of plant hosts are also briefly introduced. Moreover, potential application of effector biology in disease management and the breeding of resistant varieties is discussed.
Oomycete
Plant Immunity
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Identification
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There is a continuous arms race between pathogens and their host plants. However, successful pathogens, such as phytopathogenic oomycetes, secrete effector proteins to manipulate host defense responses for disease development. Structural analyses of these effector proteins reveal the existence of regions that fail to fold into three-dimensional structures, intrinsically disordered regions (IDRs). Because of their flexibility, these regions are involved in important biological functions of effector proteins, such as effector-host protein interactions that perturb host immune responses. Despite their significance, the role of IDRs in phytopathogenic oomycete effector-host protein interactions is not clear. This review, therefore, searched the literature for functionally characterized oomycete intracellular effectors with known host interactors. We further classify regions that mediate effector-host protein interactions into globular or disordered binding sites in these proteins. To fully appreciate the potential role of IDRs, five effector proteins encoding potential disordered binding sites were used as case studies. We also propose a pipeline that can be used to identify, classify as well as characterize potential binding regions in effector proteins. Understanding the role of IDRs in these effector proteins can aid in the development of new disease-control strategies.
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The ability to secrete effector proteins that can enter plant cells and manipulate host processes is a key determinant of what makes a successful plant pathogen. Here, we review intracellular effectors from filamentous (fungal and oomycete) phytopathogens and the host proteins and processes that are targeted to promote disease. We cover contrasting virulence strategies and effector modes of action. Filamentous pathogen effectors alter the fates of host proteins that they target, changing their stability, their activity, their location, and the protein partners with which they interact. Some effectors inhibit target activity, whereas others enhance or utilize it, and some target multiple host proteins. We discuss the emerging topic of effectors that target negative regulators of immunity or other plant proteins with activities that support susceptibility. We also highlight the commonly targeted host proteins that are manipulated by effectors from multiple pathogens, including those representing different kingdoms of life.
Oomycete
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Abstract Microbial plant pathogens use secreted effector proteins for successful infection of their host. This evolved state is rather exceptional as most microbes do not cause disease in the vast majority of plant species. An important primary activity of effectors is to interfere with a range of plant immune processes to evade and suppress pathogen detection, or to block immune signalling and downstream responses. Furthermore, effectors can enhance disease susceptibility by altering cellular processes and modulating host transcription. For most of these activities, effectors specifically target plant proteins that are central in these processes. An advanced virulence strategy is the post‐translational modification by effectors of plant targets to change their activity or stability. The knowledge gathered on the molecular mechanisms underlying effector‐triggered susceptibility of plants provides great potential for novel approaches of resistance breeding. Key Concepts Pathogens secrete and/or translocate effector proteins to promote plant disease. Besides their primary role in promoting disease, effectors or effector‐modified plant proteins can be recognised by resistance proteins to activate an effector‐triggered immune response. Many effectors block pathogen‐associated molecular pattern (PAMP)‐triggered immunity and/or effector‐triggered immunity. Other effectors rewire signalling pathways and reprogramme the plant cell to promote pathogen growth. Certain effectors can affect the activity or function of host proteins by post‐translational modifications e.g. (de)phosphorylation or targeting for proteosomal degradation.
Plant Immunity
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Plants can be colonized by fungi that have adopted highly diverse lifestyles, ranging from symbiotic to necrotrophic. Colonization is governed in all systems by hundreds of secreted fungal effector molecules. These effectors suppress plant defense responses and modulate plant physiology to accommodate fungal invaders and provide them with nutrients. Fungal effectors either function in the interaction zone between the fungal hyphae and host or are transferred to plant cells. This review describes the effector repertoires of 84 plant-colonizing fungi. We focus on the mechanisms that allow these fungal effectors to promote virulence or compatibility, discuss common plant nodes that are targeted by effectors, and provide recent insights into effector evolution. In addition, we address the issue of effector uptake in plant cells and highlight open questions and future challenges.
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Plant diseases caused by fungal pathogens are typically initiated by molecular interactions between ‘effector’ molecules released by a pathogen and receptor molecules on or within the plant host cell. In many cases these effector-receptor interactions directly determine host resistance or susceptibility. The search for fungal effector proteins is a developing area in fungal-plant pathology, with more than 165 distinct confirmed fungal effector proteins in the public domain. For a small number of these, novel effectors can be rapidly discovered across multiple fungal species through the identification of known effector homologues. However, many have no detectable homology by standard sequence-based search methods. This study employs a novel comparison method (RemEff) that is capable of identifying protein families with greater sensitivity than traditional homology-inference methods, leveraging a growing pool of confirmed fungal effector data to enable the prediction of novel fungal effector candidates by protein family association. Resources relating to the RemEff method and data used in this study are available from https://figshare.com/projects/Effector_protein_remote_homology/87965 .
Homology
Architecture domain
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Effectors are small, secreted molecules that mediate the establishment of interactions in nature. While some concepts of effector biology have stood the test of time, this area of study is ever-evolving as new effectors and associated characteristics are being revealed. In the present review, the different characteristics that underly effector classifications are discussed, contrasting past and present knowledge regarding these molecules to foster a more comprehensive understanding of effectors for the reader. Research gaps in effector identification and perspectives for effector application in plant disease management are also presented, with a focus on fungal effectors in the plant-microbe interaction and interactions beyond the plant host. In summary, the review provides an amenable yet thorough introduction to fungal effector biology, presenting noteworthy examples of effectors and effector studies that have shaped our present understanding of the field.
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