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Dissecting the functional link between immune signaling and defense-related autophagy

Reference	BB/T006102/1
Principal Investigator / Supervisor	Dr Tolga Bozkurt
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Life Sciences
Funding type	Research
Value (£)	469,751
Status	Current
Type	Research Grant
Start date	01/09/2020
End date	31/08/2023
Duration	36 months

Abstract

The Irish famine pathogen Phytophthora infestans penetrates host cells and forms haustoria that enable translocation of effector proteins. Invaded plant cell counters with a spatially confined cell-autonomous defense response known as focal immunity, a poorly understood process implicated in the concentration of immune responses around pathogen contact sites. We recently discovered that a selective form of autophagy, mediated by the autophagy cargo receptor Joka2, targets haustorium interface to contribute to plant focal immunity. This pointed to more complex functions for autophagy than the widely known degradative roles. Remarkably, Joka2 is also implicated in plant defence against bacteria and viruses. How Joka2 contributes to immunity, and the molecular mechanisms underlying defense-related selective autophagy are poorly understood. Specifically, how Joka2 is activated by the plant immune system is unknown. In this project, our goal is to characterize the molecular mechanisms underpinning Joka2-mediated immunity. We have generated unpublished data showing Joka2 interacts with MAPKs, the signaling components of the PAMP triggered immunity (PTI). Our central hypothesis is that Joka2 links PTI and autophagy pathways to boost basal plant resistance. Our working model is that Joka2 associates with MAPKs at the haustorium interface to modulate immunity by enhancing PTI outputs and/or to modulate defense-related autophagy. Consistent with this view, a mammalian orthologue of Joka2 is known to function as a signalling scaffold to regulate diverse cellular processes. By deciphering the molecular code underpinning the complexity of the Joka2 mediated autophagy, including its interactions with PTI signaling, we will gain insights into the detailed mechanisms of basal plant resistance at the genetic, biochemical and cell biological levels. The knowledge gained will enable remodelling of the defense-related autophagy machinery to counteract manipulation by pathogens.

Summary

By 2050, global food production needs to increase by 70% to feed the rapidly growing human population. Filamentous plant pathogens including oomycetes and fungi cause the most destructive crop diseases and pose a major threat to our food security. The late blight, caused by the Irish famine pathogen Phytophthora infestans, is a deadly disease of potato and tomato. Outbreaks caused by late blight, as well as the control measures undertaken to manage the disease, lead to more than £6 billion in annual losses globally. The management of the disease relies on costly agrochemicals some of which are under rigorous regulations due to environmental and health concerns. Reduced fungicide sensitivity in newly emerging strains worsen the situation. A sustainable alternative is to genetically improve resistance, a specific and targeted approach which requires a deeper understanding of plant immunity. Although plants have the genetic toolkit to fight diseases, the capacity of pathogens to adapt and evade plant immunity has constrained traditional resistance breeding. Plants defend against parasites through specialized immune sensors. Surface immune sensors, recognize molecules released by the parasites that are distinct from anything found in the plant. Activation of these surface receptors triggers immunity - known as pattern triggered immunity, or PTI. This kickstarts intricate signalling cascades that translate external immune stimuli into defense responses. The role of PTI in providing resistance to plant pathogens is well-established. However, the molecular mechanisms leading to enhanced resistance following PTI activation are not fully understood. Nevertheless, successful transfer of surface immune sensors from model plant species to crops has sparked renewed interest in understanding the innerworkings of PTI. Like other filamentous plant pathogens, the late blight pathogen invades host cells through finger-like extensions called haustoria, through which it secretes immunity-breaking factors to gain control of the invaded cells. Invaded plant cells often respond by concentrating their immune responses at the pathogen extensions to prevent further infection. Although PTI is implicated in the production of defense-compounds that are deployed towards the pathogen haustoria, the extent to which PTI regulates targeted cellular transport routes to the pathogen interface is not known. All plants and animals undergo a process of self-recycling called autophagy - this ensures that cellular components are degraded when necessary, while preserving the building-blocks, that can be reused in other cellular processes. Recently, ourselves and others discovered that autophagy is activated to contribute to defense against Phytophthora infestans, bacteria and viruses. We later discovered that defense-related autophagy machinery is diverted to pathogen interface to contribute to targeted immune responses. This pointed to more complex functions for autophagy than the widely known recycling roles. However, how defense-related autophagy pathways are activated and regulated at the molecular level, as well as the extent to which it is altered by PTI is unknown. In this proposal, we aim to characterize the molecular mechanisms that govern defense-related autophagy. We have generated substantial preliminary data that a regulator of defense-related autophagy machinery interacts with the PTI signaling components. Hence, we will specifically focus on investigating the molecular interplay between PTI and defense-related autophagy pathways to elucidate the molecular events leading to enhanced disease resistance. By decrypting these mechanisms, we will generate fundamental knowledge that will be helpful to remodel plant immune system towards improved pathogen resistance. This work will have far-reaching implications, as the defense-related autophagy machinery provides resistance to a diversity of important pathogens.

Impact Summary

The project will provide insight into a recently discovered defense-related autophagy pathway in agronomically important solanaceous plants. This involves a selective autophagy cargo receptor, which interacts with the signaling components of the PAMP triggered immunity (PTI). The project will dissect the mechanisms by which defense-related autophagy is functionally linked to PTI. Thus, the project bridges two processes previously only considered in isolation. By crossing the boundaries of defence related processes, the work pushes the field by moving away from a reductionist view on immunity, and towards a holistic view of plant immune responses and cellular processes. Defense-related autophagy is implicated in resistance against important plant pathogens such as oomycetes, bacteria and viruses. Thus, this work will have a broader impact not only because it will build on the emerging paradigm of defense-related autophagy, but also is applicable to multiple pathosystems. The knowledge produced will contribute to the scientific leadership of the UK in plant pathology and biotechnology, and will broadly impact BBSRCs strategic priority area of food security. Proposed research will benefit following non-academic units; i. Ag-Biotechnology industry The Ag-Biotechnology industry will gain new insights into the functioning of basal plant resistance mediated by autophagy and PTI. The knowledge gained on the mechanistic interplay between PTI signalling and autophagy machinery, which is actively targeted by pathogens, will lead to discovery of novel strategies and target genes for engineering disease resistance. In particular, remodelling of defense-related autophagy to avoid pathogen manipulation should prove a useful method for improving pathogen resistance. In plants, selective autophagy also plays critical roles in stress tolerance and development. Therefore, the project will generate conceptual knowledge in selective autophagy that will underpin future efforts of generating stress tolerant plants which can better cope with environmental fluctuations. The plant-based expression systems have been successfully used for biopharming of clinically and industrially valuable recombinant proteins including the Ebola virus vaccine. However, factors affecting protein degradation negatively impact large-scale biopharming. Because autophagy is a major cellular degradation pathway, knowledge gained on this will have a huge impact in biopharming practices. ii. Breeders The proposed work will provide new perspectives for exploiting crucial components of basal plant immunity in plant breeding. Breeders will gain new knowledge on key players of immunity and genes involved in autophagy mediated stress tolerance. This should help plant breeding practices by ensuring that essential components of immunity are maintained in the newly generated lines. iii. The public Our ultimate aim is to help produce cheaper and healthier food. We expect that our efforts to understand basic principles of plant immunity will lead to improved food productivity by preventing crop losses and reducing the usage of costly and environmentally hazardous agrochemicals. iv. The environment The environment will benefit from reduced usage of agrochemicals. Efforts to improve genetic resistance as an alternative to chemical control of plant diseases will have a positive influence on the environment, considering the health concerns due to excessive usage agrochemicals. vi. Undergraduate and postgraduate students Students enrolled in Imperial College Biological Sciences will benefit from having access to the proposed cutting-edge program. I have already prepared a practical course for the 3rd year students involving plant immune activation. Additionally, motivated students will have the chance to participate in the proposed research program through summer placements and final year projects.

Committee	Research Committee B (Plants, microbes, food & sustainability)
Research Topics	Crop Science, Microbiology, Plant Science
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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