Innate Immunity is the most ancient and evolutionarily conserved central defense system that distinguishes host-self from non-self microbial pathogens in plants, animals and humans. It provides the first line of inducible defense against infectious diseases and underlies the prevention of constant and omnipresent microbial invasion. A key function of innate immunity is the detection of microbe-associated molecular patterns (MAMPs), e.g., bacterial flagellin and fungal chitin, by pattern recognition receptors (PRRs) to launch appropriate defense responses. Recent discoveries have revealed remarkable convergent evolution in the recognition of diverse MAMPs by leucine- rich-repeat (LRR) receptors and the activation of multiple MAPK cascades in plants, animals and humans. Despite the universal and essential involvement of MAPK cascades in mediating MAMP signaling in plants, worms, flies, mammals and humans, the molecular mechanisms underlying the intertwined signaling webs remain mostly elusive due to the complexity of functional redundancy, mutant lethality and shared components in distinct signaling pathways. How the conserved immune responses are integrated with stress signaling sharing common regulators remains unclear. The goal of this research project is to establish a regulatory framework for the convergent MAMP and stress signaling mechanisms using Arabidopsis thaliana as a plant model system. The proposed experiments aim to integrate powerful functional genomic screens with comprehensive molecular, biochemical, cellular, genetic, genomic and chemical analyses to 1) discover new molecular links between the flagellin receptor (FLS2) complexes and MAPK cascades, 2) systematically elucidate the transcriptional network in dynamic and diverse plant defense responses, and to 3) uncover a previously unrecognized connection between TOR kinase signaling and innate immunity. Specifically, the project will focus on characterizing and integrating the newly discovered functions of RLCKs (receptor-like cytoplasmic kinases) in FLS2 signaling, flg22-triggered transcriptional networks modulated by key transcription activators and repressors, and novel TOR kinase substrates in stress and immune signaling. The project on uncovering the novel receptor-MAPK, calcium and TOR signaling mechanisms will establish new conceptual understanding in the regulation of immune responses and transcriptional networks beyond the plant system.
Aim 1. Analyze new functions of diverse RLCKs in FLS2-MAPKKK signaling complexes Aim 2. Dissect the dynamic transcriptional network in convergent MAMP signaling Aim 3. Explore novel TOR kinase substrates in connecting stress and immune signaling

Public Health Relevance

The versatile innate immune system underlies the ancient and evolutionarily conserved mechanisms for prevention of constant and omnipresent microbial invasion, and provides the first line of inducible defense against infectious diseases in plants, animals and humans. A key function of innate immunity is the detection of microbe-associated molecular patterns and danger signals to launch appropriate defense responses. The proposed research on pattern recognition receptor kinase signaling complexes, intertwined protein kinase cascades and transcriptional networks will discover novel and fundamental molecular mechanisms in immune and stress signaling, and provide innovative tools for future improvement of agriculture, environment and renewable energy production, as well as human health in treating infectious, inflammatory and autoimmune diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Marino, Pamela
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Massachusetts General Hospital
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