Retrograde signaling is an essential organelles-to-nucleus communication pathway, central to maintenance of cellular homoeostasis in response to developmental and environmental inputs. We have identified the first stress-specific plastid-to-nucleus retrograde signaling metabolite, methylerythritol cyclodiphosphate (MEcPP), an isoprenoid precursor produced by the non-mevalonate methylerythritol phosphate (MEP) pathway. This is a conserved signaling pathway present in plants, pathogenic bacteria and the parasite, malaria, but absent in animals. As such, it has provided a validated target for the development of antibacterial and antimalarial agents. The long-term goal of our research is to delineate the perception and signal transduction components of MEcPP-mediated signaling cascade. This competitive renewal proposal specifically aims at delineating: I. Cellular components of the MEcPP retrograde signaling pathway To identify the components responsible for the perception and transduction of the MEcPP signal, we will initially characterize the mutated genes in the two classes of suppressor lines that, despite their equally constitutively elevated MEcPP levels, are either almost fully or only partially incapable of inducing MEcPP response genes. Systematic characterization of these perception/signaling network components will provide fundamental information regarding the underlying molecular mechanisms that link a single retrograde signaling molecule, MEcPP, to its targeted ensemble of genes. II. Molecular link between MEcPP and unfolded protein response in the ER Combined global transcriptome and proteome profiling, together with molecular genetics and pharmacological approaches, has enabled us to identify MEcPP as an inducer of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER). We will decipher the MEcPP mechanism of action in induction of the UPR, and conversely delineate the role of the UPR in MEcPP-mediated responses. This finding ushers novel insight into uncharted territories of interorganellar signaling, and will provide a deeper understanding of key role of UPR in controlling principal mechanisms supporting robustness. III. Governing components of stromule formation Imaging analyses of plants expressing a construct containing three chimeric marker genes that label plastids with CFP, ER with YFP, and the nucleus with mCherry, has established a direct correlation between enhanced MEcPP levels and increased presence of induced dynamic chloroplast tubular extensions called stromules?, that extend from plastids to ER to nucleus. We will perform comparative proteomic analyses of genotypes with varying numbers of stromules to identify cellular machineries responsible for their formation and to test the potential role of stromules as communication conduits.

Public Health Relevance

We have identified an intermediate of a metabolic pathway that is absent in animals but is present in plants, Eubacteria and Apicomplexan. This metabolite also functions as a plastid-to-nucleus (retrograde) stress signal, however through a poorly understood mechanism. As such, successful execution of the proposed study will not only provide fundamental insight into the mechanism of retrograde signaling, but also offers novel candidates for development of new antibiotics and antimalarial agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM107311-05
Application #
9522763
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2013-09-05
Project End
2022-02-28
Budget Start
2018-05-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Other Basic Sciences
Type
Earth Sciences/Resources
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Zhang, Meixiang; Chiang, Yi-Hsuan; Toruño, Tania Y et al. (2018) The MAP4 Kinase SIK1 Ensures Robust Extracellular ROS Burst and Antibacterial Immunity in Plants. Cell Host Microbe 24:379-391.e5
Wang, Jin-Zheng; Dehesh, Katayoon (2018) ER: the Silk Road of interorganellar communication. Curr Opin Plant Biol 45:171-177
Jiang, Jishan; Rodriguez-Furlan, Cecilia; Wang, Jin-Zheng et al. (2018) Interplay of the two ancient metabolites auxin and MEcPP regulates adaptive growth. Nat Commun 9:2262
Wang, Jin-Zheng; Li, Baohua; Xiao, Yanmei et al. (2017) Initiation of ER Body Formation and Indole Glucosinolate Metabolism by the Plastidial Retrograde Signaling Metabolite, MEcPP. Mol Plant 10:1400-1416
Bjornson, Marta; Balcke, Gerd Ulrich; Xiao, Yanmei et al. (2017) Integrated omics analyses of retrograde signaling mutant delineate interrelated stress-response strata. Plant J 91:70-84
He, Xiang; Jiang, Jishan; Wang, Chang-Quan et al. (2017) ORA59 and EIN3 interaction couples jasmonate-ethylene synergistic action to antagonistic salicylic acid regulation of PDF expression. J Integr Plant Biol 59:275-287
Lemos, Mark; Xiao, Yanmei; Bjornson, Marta et al. (2016) The plastidial retrograde signal methyl erythritol cyclopyrophosphate is a regulator of salicylic acid and jasmonic acid crosstalk. J Exp Bot 67:1557-66
Bjornson, Marta; Dandekar, Abhaya; Dehesh, Katayoon (2016) Determinants of timing and amplitude in the plant general stress response. J Integr Plant Biol 58:119-26
Benn, Geoffrey; Dehesh, Katayoon (2016) Quantitative Analysis of Cis-Regulatory Element Activity Using Synthetic Promoters in Transgenic Plants. Methods Mol Biol 1482:15-30
Benn, Geoffrey; Bjornson, Marta; Ke, Haiyan et al. (2016) Plastidial metabolite MEcPP induces a transcriptionally centered stress-response hub via the transcription factor CAMTA3. Proc Natl Acad Sci U S A 113:8855-60

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