Project Summary/Abstract NPR1 (NONEXPRESSOR OF PATHOGENSIS-RELATED GENES 1) is a master immune regulator in plants. It orchestrates systemic acquired resistance (SAR) by activating PATHOGENESIS-RELATED (PR) genes in response to induction of salicylic acid (SA) during the plant response to pathogenic challenges. Extensive genetic and biochemical studies have shown that NPR1 is a receptor of SA. SA activation of NPR1 triggers genome- wide transcriptional reprograming via NPR1 interactions with a variety of transcription activators and repressors. NPR1 itself is regulated by redox agents, and its proteolytic turnover has profound implications in a wide range of biological functions, including circadian rhythm and resistance to proteotoxic stress in the endoplasmic reticulum. Despite the essential role of NPR1 in plant biology, the molecular details underlying the myriad of NPR1 functions have remained largely unknown. Building upon our initial success in elucidating the structure of apo NPR1 using single-particle cryoEM, here we propose to elucidate the molecular basis of the NPR1 function in plants. Specifically, we will address (1) how SA activates NPR1, (2) how NPR1 interacts with transcription factors and regulators, and (3) how NPR1 is degraded. Information gained from these studies will provide the much-needed mechanistic insights into the SA-NPR1 signaling cascade in plants and help develop disease- resistant crops. As SA is the principle metabolite of aspirin, such knowledge may also contribute to a better understanding of the well-documented medicinal benefits of SA and analogs in humans.

Project Narrative (Public Health Relevance Statement) In spite of the essential role of NPR1 (NONEXPRESSOR OF PATHOGENSIS-RELATED GENES 1) as a master regulator of the salicylic acid (SA)-mediated immune response in plants, the molecular mechanism of its function has remained poorly understood. Genetically engineered crops through enhancement of the NPR1-mediated innate immunity display broad-spectrum disease resistance without compromising plant fitness, leading to a decreased usage of pesticides and reduction of the selective pressure for pesticide-resistant pathogens. As SA and derivatives, such as aspirin (acetylsalicylate), have numerous health benefits in humans, including fever reduction and pain relief, as well as decreased death tolls from cardiovascular diseases and cancers, a thorough understanding the SA-NPR1 signaling pathway in plants may also bear significant implications in understanding the medicinal consequence of these molecules against a variety of human diseases.