Salicylic acid (SA) and derivatives, such as aspirin, have a long list of medicinal effects, which include not only fever reduction and pain relief, but also prevention of cardiovascular diseases and significant reduction of deaths by various cancers and symptoms of type II diabetes. However, the molecular mechanisms underlying this wide range of medicinal effects of salicylates are not completely known. SA is a plant hormone that controls the plant immune response, systemic acquired resistance (SAR). SAR is a broad-spectrum resistance that can be induced by a local pathogen challenge that results in programmed cell death (PCD) or by exogenous application of SA. SA signaling requires the function of the transcription cofactor NPR1 protein. However, despite years of research, major questions remain with regard to (1) how SA synthesis is regulated in plants and (2) what the receptor is for SA. Through Aim 1, the regulation of SA biosynthesis genes by a circadian clock component, CHE, and by transcription factors specifically targeted by pathogen effectors will be studied. The hypothesis that SA levels in plants are intimately linked with the cellular redox stat which influences the circadian clock, NPR1 nuclear translocation, and disease resistance will be tested. Aim 2 will focus on the characterization of NPR1 paralogs, NPR3 and NPR4, two BTB-domain containing adaptors for Cullin 3 E3 ubiquitin ligase, as SA receptors. SA binds to NPR3 and NPR4 specifically and regulates their interactions with NPR1 to control proteasome-mediated degradation of NPR1. The dynamics of these interactions will be examined in both local and systemic tissues upon pathogen challenge to prove the hypothesis that NPR1 is degraded in the infected cells to allow pathogen effectors-triggered PCD and resistance, and that NPR1 accumulates in the cells surrounding the infection site to prevent the spread of PCD and to promote SAR. The mechanism by which NPR1 inhibits PCD will be tested through study of NPR1-transcriptional targets with anti-PCD activities. Understanding SA production and perception in plants will provide new insights into the medicinal effects of salicylates because SA affects cellular redox and cell death and survival, which are processes fundamental to all living organisms.