Adverse environmental conditions as well as physiological situations requiring enhanced secretory protein synthesis can cause an imbalance between demand and capacity of protein synthesis at the endoplasmic reticulum (ER). The ER can sense stress and restore homeostasis by invoking a protective signaling pathway known as the unfolded protein response (UPR). To initiate UPR, yeast largely relies on a linear arm based on the action of a conserved sensor, Ire1p. During the course of evolution, the suite of UPR arms harnessed additional sensors to accommodate more specific responses in a multicellular context. A major challenge in UPR studies is now to understand the biological role of the various UPR arms in intact organisms to define how the UPR signaling network functions to direct diverse cell-fate decisions in development and response to biotic and abiotic stress. The conservation of plant and metazoan UPR and the availability of powerful genomics and molecular tools render the model plant Arabidopsis thaliana an appealing system in which to address these questions. In plants, the UPR is thought to play a major role in various stress situations, but the understanding of plant UPR mechanisms is still limited. In Arabidopsis, two membrane-tethered blip transcription factors, bZIP28 and bZIP60, and a subunit of the conserved heterotrimeric G protein complex, AGB1, have been shown to function as regulators of plant UPR, but little is known about the molecular components of the UPR arms controlled by these mediators. We have recently established a direct involvement of AtIRE1 in ER stress response and in growth. These findings will enable us to explore the role of IRE1 in combination with other key players of plant UPR to develop a model that links UPR signaling during stress responses with growth and development in vivo in a multicellular context. The immediate goals of this proposal therefore are 1) to elucidate conserved and plant-specific features in the signal transduction pathway controlled by AtIRE1;2) to define the role of the UPR arms in growth, development, and various conditions of stress;and 3) to identify the target genes corresponding to each UPR arm to define downstream effectors and to elucidate how the UPR signaling arms intersect with each other. Adding plants as an evolutionarily distinct and tractable model for the study of the UPR in multicellular organisms is important because it will allow comparing and contrasting plant, yeast, and animal UPRs, and thus will provide significant insights into these systems, adding to our fundamental understanding of eukaryotic cell biology at large. To achieve our goals we will integrate functional genomics with in vitro assays and transcriptomics. We will be able to establish how plants depend on the UPR signaling network during growth and development and in response to stress conditions that require enhanced secretory protein synthesis. Our results will not only enhance our understanding of human growth and disease, they will also permit the development of UPR drugs in a tractable multicellular model, and contribute to our understanding of limiting factors in agricultural processes and plant biotechnology designed to sustain food security on earth.

Public Health Relevance

This project addresses several questions related to the mechanisms that are in place to defend multicellular organisms from diseases and conditions caused by insufficient ability to regulate secretory protein load;in particular, we aim to understand what mechanisms are in place to respond to biotic and abiotic stress, and how such mechanisms are coordinated during stress, growth, and development. The specific multicellular model being examined in this study is a plant, Arabidopsis thaliana, for which a large suite of genomics and molecular tools make feasible genetic and molecular analyses that are very difficult to perform in humans. Through the development of the project, we will be able to enrich general knowledge of stress responses in multicellular organisms through the discovery of plant-specific features, which may lead to improved agricultural processes and plant biotechnology designed to sustain food security on earth;importantly also, because key stress responses are similar between plants and humans, we will learn about conserved mechanisms and thus improve our understanding of human disease and growth.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Wehrle, Janna P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Michigan State University
Other Basic Sciences
Schools of Arts and Sciences
East Lansing
United States
Zip Code
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

Showing the most recent 10 out of 24 publications