Salicylic Acid in Immunity and Health: A Small Phytohormone with Big Physiological Impacts

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The essence of an immune system is to ensure defense against pathogens without collateral damage to self. In plants, this is accomplished, in part, through the regulation of the immune signal salicylic acid (SA). Production of SA during the effector-triggered immunity (ETI) is associated with programmed cell death (PCD) of the infected cells to restrict pathogen growth at the site of infection and survival of distal cells with broad-spectrum systemic acquired resistance (SAR). This binary function of SA is achieved through activities of NPR1. NPR1 is not only a master immune regulator, but also involved in key cellular functions, such as the circadian clock. In the absence of pathogen challenge, SA is rhythmically produced through the direct regulation of the clock component CHE and subsequently controls the nuclear translocation of NPR1. NPR1 is required for the expression of not only SA-mediated defense genes, but also both morning and evening clock genes. Hence, the npr1 mutant is hypersusceptible to infection and has significantly dampened clock activities. However, how PCD is executed at the site of infection, how NPR1 inhibits PCD in distal cells and promotes SAR, and what role the circadian clock plays in regulating SAR are long- standing fundamental questions. This project will investigate how the nuclear pore complex permeability and the nuclear Ca2+ are specifically increased in executing ETI/PCD in infected cells and test the hypothesis that NPR1 reprograms the defense transcriptome and promotes survival of distal cells as a substrate adaptor for the Cul3 ubiquitin ligase complex through the formation of SA-induced NPR1 condensates in both the nucleus and the cytoplasm. The project will also determine the mechanism by which CHE is activated in systemic tissue to induce SA synthesis and explain why a clock component is involved in regulating this key step of SAR. Finally, genetic analysis will be performed to provide the molecular basis for the clock-mediated gating of the SA immune response towards the morning in avoiding plant desiccation at night and to highlight the importance of time-of-the-day chemical application in agriculture and in medicine for maximizing efficacy and reducing side effects. This continuously developing project fits the NIGMS mission of “understanding the principles, mechanisms, and processes that underlie living organisms, often using research models” and the MIRA funding model. Besides its obvious significance to basic biology and agriculture, the project may have even broader implications because SA is the oldest herbal medicine known to mankind. In recent years, aspirin (acetylated SA) has been repurposed in treating cardiovascular diseases and certain types of cancer (e.g., colon cancer). Non-acetylated SA derivatives have shown promising results in treating type II diabetes in clinical trials. However, the underlying mechanisms for these diverse medicinal effects are not completely understood and the issue over how to enhance the drug efficacy while reducing the side effect (e.g., bleeding) has to be addressed.