In living organisms sugars not only provide energy and carbon skeletons but also act as evolutionarily conserved signaling molecules. The three major soluble sugars in plants are sucrose, glucose, and fructose. Information on plant glucose and sucrose signaling is available, but to date no fructose-specific signaling pathway has been reported. In this study, sugar repression of seedling development was used to study fructose sensitivity in the Landsberg erecta (Ler)/Cape Verde Islands (Cvi) recombinant inbred line population, and eight fructose-sensing quantitative trait loci (QTLs) (FSQ1-8) were mapped. Among them, FSQ6 was confirmed to be a fructose-specific QTL by analyzing near-isogenic lines in which Cvi genomic fragments were introgressed in the Ler background. These results indicate the existence of a fructose-specific signaling pathway in Arabidopsis. Further analysis demonstrated that the FSQ6-associated fructose-signaling pathway functions independently of the hexokinase1 (HXK1) glucose sensor. Remarkably, fructosespecific FSQ6 downstream signaling interacts with abscisic acid (ABA)-and ethylene-signaling pathways, similar to HXK1-dependent glucose signaling. The Cvi allele of FSQ6 acts as a suppressor of fructose signaling. The FSQ6 gene was identified using mapbased cloning approach, and FSQ6 was shown to encode the transcription factor gene Arabidopsis NAC (petunia No apical meristem and Arabidopsis transcription activation factor 1, 2 and Cup-shaped cotyledon 2) domain containing protein 89 (ANAC089). The Cvi allele of FSQ6/ANAC089 is a gain-of-function allele caused by a premature stop in the third exon of the gene. The truncated Cvi FSQ6/ ANAC089 protein lacks a membrane association domain that is present in ANAC089 proteins from other Arabidopsis accessions. As a result, Cvi FSQ6/ANAC089 is constitutively active as a transcription factor in the nucleus. I n plants, sugars provide the energy and carbon skeletons needed for growth and in addition act as crucial signaling molecules that affect growth, development, and response to the (a)biotic environment (1-3). Plant cells harbor sugar-sensing and -signaling systems that regulate the expression of thousands of genes and control the metabolic processes needed for growth (2-4). These sugar-response systems are known to interact with other signaling pathways, such as those for light, phytohormones, stress, and nutrients (1).The neutral sugars sucrose, glucose, and fructose are central to metabolism in plants and in other organisms as well. So far, detailed information is available only on glucose sensing, and it has been shown that the hexokinase 1 (HXK1) enzyme acts as a glucose sensor (5, 6). Sucrose-specific signaling also was demonstrated because the effect of sucrose cannot be mimicked by glucose and/or fructose (7), but so far no information on sucrosesensing systems is available. A signaling function for fructose has been proposed (8, 9), but no convincing experimental evidence on such fructose-specific signaling is available.In Arabidopsis ea...