Glucose fuels life and is a central nutrient signal for growth regulation in a broad range of organisms from E. coli, yeasts to plants and humans. Despite the essential and multifaceted regulatory roles of glucose in gene expression, physiology, metabolism, cell proliferation, growth and development, and human diseases, the molecular and cellular mechanisms of glucose signaling remain elusive in multicellular plants and animals. Our research in the model plant Arabidopsis thaliana has provided compelling molecular, chemical and genetic evidence that hexokinase1 (HXK1) and target-of-rapamycin (TOR) kinase are two evolutionarily conserved master regulators in glucose signaling, which integrate direct glucose sensing and glucose-driven energy signaling to orchestrate transcriptional networks and plant growth in response to environmental cues. Our recent findings uncover two surprising and distinct functions of Arabidopsis HXK1 that mediate glucose signaling without its catalytic activity. In leaves, HXK1 senses excess glucose at low nitrate and acts in the nucleus to modulate transcriptional reprogramming. In nitrate sufficient conditions, HXK1 plays an additional novel function in direct binding and mobilization of the phytohormone auxin to promote cell and organ size and growth. We have also developed new chemical genetic tools to discover a previously unrecognized central role of glucose-TOR signaling in controlling stem/progenitor cell proliferation in meristem activation and postembryonic plant growth. The goal of this research project is to elucidate the molecular mechanisms of glucose signaling controlled by the glucose sensor HXK1 and the energy sensor TOR kinase in Arabidopsis. The proposed experiments are designed to integrate molecular, biochemical, cellular, genetic, and genomic approaches to reach a comprehensive understanding on major branches of glucose signaling mechanisms central to plant growth, including the unconventional role of HXK1 in transcriptional reprogramming, the novel function of HXK1 in auxin binding and mobilization, as well as the transcriptional network modulated by glucose-TOR signaling. The project on uncovering the novel glucose-HXK1 and glucose-TOR signaling mechanisms will establish new paradigms in glucose responses and regulations in plants and animals, and build a new conceptual framework to enhance our understanding of the molecular and cellular mechanisms of glucose signaling from plants to humans.
Three Specific Aims are:
Aim 1. Elucidate the regulatory mechanism of HXK1 functions as a nuclear glucose sensor.
Aim 2. Characterize the novel HXK1 functions in auxin and glucose synergism.
Aim 3. Define the novel glucose-TOR signaling network gating the cell cycle entry.

Public Health Relevance

Our discoveries on the glucose signaling networks controlled by two evolutionarily conserved master regulators, the glucose sensor HXK1 and the energy sensor TOR, will unravel the missing links in nutrient regulation of transcription, cell and organ size, and cell proliferation in plant growth, which are the core to agricultural and bioenergy productivity for sustaining all human life and the ecosystems on the planet. The new concepts and mechanisms represent a paradigm shift in current research in glucose signaling from plants to humans, and may aid the elucidation of transcriptional networks coupling metabolic regulation and proliferation of stem/progenitor cells central to the health, longevity and diseases in animals and humans. The novel and surprising results from the proposed studies will lead to fundamental knowledge and sustained impact on nutrient signaling central to plant biology and human health.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM060493-13A1
Application #
8703217
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Reddy, Michael K
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Li, Lei; Sheen, Jen (2016) Dynamic and diverse sugar signaling. Curr Opin Plant Biol 33:116-125
Cheng, Zhenyu; Li, Jian-Feng; Niu, Yajie et al. (2015) Pathogen-secreted proteases activate a novel plant immune pathway. Nature 521:213-6
Xiong, Yan; Sheen, Jen (2015) Novel links in the plant TOR kinase signaling network. Curr Opin Plant Biol 28:83-91
Li, Jian-Feng; Zhang, Dandan; Sheen, Jen (2015) Targeted plant genome editing via the CRISPR/Cas9 technology. Methods Mol Biol 1284:239-55
Sheen, Jen (2014) Master Regulators in Plant Glucose Signaling Networks. Journal of plant biology = Singmul Hakhoe chi 57:67-79
Xiong, Yan; Sheen, Jen (2014) The role of target of rapamycin signaling networks in plant growth and metabolism. Plant Physiol 164:499-512
Wu, Hung-Yi; Liu, Kun-Hsiang; Wang, Yi-Chieh et al. (2014) AGROBEST: an efficient Agrobacterium-mediated transient expression method for versatile gene function analyses in Arabidopsis seedlings. Plant Methods 10:19
Hamel, Louis-Philippe; Sheen, Jen; Seguin, Armand (2014) Ancient signals: comparative genomics of green plant CDPKs. Trends Plant Sci 19:79-89
Li, Jian-Feng; Zhang, Dandan; Sheen, Jen (2014) Epitope-tagged protein-based artificial miRNA screens for optimized gene silencing in plants. Nat Protoc 9:939-49
Zhou, Jinggeng; Wu, Shujing; Chen, Xin et al. (2014) The Pseudomonas syringae effector HopF2 suppresses Arabidopsis immunity by targeting BAK1. Plant J 77:235-45

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