Protein synthesis in the endoplasmic reticulum (ER) can be dramatically upregulated under stress conditions. To avoid jamming of protein translocation and folding, the ER senses early indicators of such stress conditions and responds with the so-called unfolded protein response (UPR). This is an ancient signal transduction pathway that leads to the rapid replenishment of ER chaperones and other folding factors and avoids energy- requiring repair mechanisms before committing to apoptosis. The UPR is critical to sustain cell growth and development and to combat disease and abiotic stress. Interestingly, the efficacy of the UPR varies largely among individuals of the same species, but the underlying molecular causes are unknown. To initiate the UPR, yeast relies heavily on the action of a conserved ER stress sensor, Ire1p. During the course of evolution, the suite of UPR sensors has expanded to accommodate more specific responses in a multicellular context. The basic activation mechanisms and general function of the ER stress sensors are largely known from in vitro studies and cell culture analyses. However, how the UPR regulators work coordinately to sustain healthy cell growth and development with a minimum of energy costs is unknown. We wish to address this fundamental question in Arabidopsis thaliana, because of the conservation of plant and metazoan UPRs, the vast availability of genetic diversity and genomics resources for this model species, and the relevance of the plant kingdom as a source for renewable energy, food, and materials. The immediate goals of this proposal are 1) to define the molecular determinants underlying intra-specific UPR variability using natural populations with broad genetic diversity, 2) to understand the mechanisms that control homeostasis among the various UPR pathways in vivo, and 3) to define non-conventional mechanisms that modulate ER stress responses in intact organisms. To achieve our goals, we will pursue our genome-wide studies to characterize UPR diversity as well as our functional genomics analyses to define the mechanisms for homeostasis of the UPR signaling pathways in vivo. We will also use advanced next-generation sequencing strategies to define post-transcriptional modulation of the UPR. Our results will lead to a broad and deep understanding of the complexity of the UPR signaling network during ER stress in the context of complex multicellular organisms. Adding plants as an evolutionarily distinct and tractable model for the study of the UPR in complex organisms is also important because it will allow comparing and contrasting plant, yeast, and animal UPRs, and thus will provide significant insights into these systems, adding to the fundamental knowledge of eukaryotic cell biology at large. Our results will not only enhance our understanding of human growth and disease, they will also permit the development of drugs in a tractable multicellular model, and contribute to our knowledge of limiting factors in agricultural processes and plant biotechnology designed to sustain food security on earth.

Public Health Relevance

Under stress conditions, the biosynthetic capacity of an essential organelle, the endoplasmic reticulum (ER), is heavily challenged, leading to a situation, known as 'ER stress', which is potentially lethal for the cell and is linked to numerous human diseases. This project aims to define the molecular differences that cause variability in the ability of individuals to respond to ER stress and to identify new factors and mechanisms that facilitate cell survival in conditions that affect ER homeostasis using a model plant species, for which a large suite of genomics and molecular tools make feasible a broad range of genetic and molecular analyses of ER stress responses. Through the development of the project, we will enrich general knowledge of ER stress responses; because key ER stress responses are similar between plants and humans, we will learn about conserved mechanisms and thus improve our understanding of human disease, and through the discovery of plant- specific features we will enable improvement of agricultural processes and plant biotechnology designed to sustain food security on earth.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Phillips, Andre W
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Michigan State University
Other Basic Sciences
Schools of Arts and Sciences
East Lansing
United States
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Lai, Ya-Shiuan; Renna, Luciana; Yarema, John et al. (2018) Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum. Proc Natl Acad Sci U S A 115:E5203-E5212
Brandizzi, Federica (2018) Transport from the endoplasmic reticulum to the Golgi in plants: Where are we now? Semin Cell Dev Biol 80:94-105
Lai, Ya-Shiuan; Stefano, Giovanni; Zemelis-Durfee, Starla et al. (2018) Systemic signaling contributes to the unfolded protein response of the plant endoplasmic reticulum. Nat Commun 9:3918
Angelos, Evan; Brandizzi, Federica (2018) NADPH oxidase activity is required for ER stress survival in plants. Plant J 96:1106-1120
Ruberti, Cristina; Lai, YaShiuan; Brandizzi, Federica (2018) Recovery from temporary endoplasmic reticulum stress in plants relies on the tissue-specific and largely independent roles of bZIP28 and bZIP60, as well as an antagonizing function of BAX-Inhibitor 1 upon the pro-adaptive signaling mediated by bZIP28. Plant J 93:155-165
Ruberti, Cristina; Brandizzi, Federica (2018) Unfolded Protein Response in Arabidopsis. Methods Mol Biol 1691:231-238
Meng, Zhe; Ruberti, Cristina; Gong, Zhizhong et al. (2017) CPR5 modulates salicylic acid and the unfolded protein response to manage tradeoffs between plant growth and stress responses. Plant J 89:486-501
Angelos, Evan; Ruberti, Cristina; Kim, Sang-Jin et al. (2017) Maintaining the factory: the roles of the unfolded protein response in cellular homeostasis in plants. Plant J 90:671-682
Kim, Sang-Jin; Zemelis-Durfee, Starla; Wilkerson, Curtis et al. (2017) In Brachypodium a complex signaling is actuated to protect cells from proteotoxic stress and facilitate seed filling. Planta 246:75-89
Zhang, Lingrui; Chen, Hui; Brandizzi, Federica et al. (2015) The UPR branch IRE1-bZIP60 in plants plays an essential role in viral infection and is complementary to the only UPR pathway in yeast. PLoS Genet 11:e1005164

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