At the Crossroads of Survival and Death: The Reactive Oxygen Species–Ethylene–Sugar Triad and the Unfolded Protein Response

Proteotoxic stress, or the accumulation of unfolded or misfolded proteins, occurs in response to a multitude of (a)biotic stresses and in multiple subcellular compartments, including the ER, chloroplasts, and mitochondria.The unfolded protein response or UPR is an evolutionary conserved mechanism in eukaryotes to cope with ER stress. In plants, the basic machinery for this response has been elucidated recently, but the molecular players involved in UPR, originating in other organelles, deserve scrutiny.Reactive oxygen species (ROS), ethylene (ETH), and sugars, are crucial players in stress responses. Upon proteotoxic stress, they act both up- and downstream of UPR. Upon stress, a trade-off between plant growth and defense responses defines the capacity for survival. Stress can result in accumulation of misfolded proteins in the endoplasmic reticulum (ER) and other organelles. To cope with these proteotoxic effects, plants rely on the unfolded protein response (UPR). The involvement of reactive oxygen species (ROS), ethylene (ETH), and sugars, as well as their crosstalk, in general stress responses is well established, yet their role in UPR deserves further scrutiny. Here, a synopsis of current evidence for ROS–ETH–sugar crosstalk in UPR is discussed. We propose that this triad acts as a major signaling hub at the crossroads of survival and death, integrating information from ER, chloroplasts, and mitochondria, thereby facilitating a coordinated stress response. Upon stress, a trade-off between plant growth and defense responses defines the capacity for survival. Stress can result in accumulation of misfolded proteins in the endoplasmic reticulum (ER) and other organelles. To cope with these proteotoxic effects, plants rely on the unfolded protein response (UPR). The involvement of reactive oxygen species (ROS), ethylene (ETH), and sugars, as well as their crosstalk, in general stress responses is well established, yet their role in UPR deserves further scrutiny. Here, a synopsis of current evidence for ROS–ETH–sugar crosstalk in UPR is discussed. We propose that this triad acts as a major signaling hub at the crossroads of survival and death, integrating information from ER, chloroplasts, and mitochondria, thereby facilitating a coordinated stress response. The sessile nature of plants implies that they are inherently subject to changing environments. As such, they need to cope with a variety of (a)biotic stresses. These harmful conditions lead to a set of shared but also distinct responses that can include oxidative stress (see Glossary), osmotic or ionic imbalances, and changes in cellular components, all of which modify the physiological status. Growth and development are hindered under such conditions, either directly, for instance by oxidative damage of essential biomolecules, or indirectly, through reprogramming of energy metabolism. In particular, the functioning of chloroplasts and mitochondria, the 'powerhouses' of the cell, is disturbed upon stress. The associated changes in carbohydrate status and ultimately energy levels, affect growth, but probably also serve as important stress signals (Figure 1, Key Figure) [1.Janse van Rensburg H.C. et al.Autophagy in plants: both a puppet and a puppet master of sugars.Front. Plant Sci. 2019; 10: 14Crossref PubMed Scopus (27) Google Scholar]. As such, mitochondria and chloroplasts act as central hubs that integrate external and internal signals to coordinate growth [2.Chan K.X. et al.Learning the languages of the chloroplast: retrograde signaling and beyond.Annu. Rev. Plant Biol. 2016; 67: 25-53Crossref PubMed Scopus (262) Google Scholar, 3.Meng X. et al.Mitochondrial signalling is critical for acclimation and adaptation to flooding in Arabidopsis thaliana.Plant J. 2020; 103: 227-247Crossref PubMed Scopus (15) Google Scholar, 4.Wu G. et al.Control of retrograde signalling by protein import and cytosolic folding stress.Nat. Plants. 2019; 5: 525-538Crossref PubMed Scopus (46) Google Scholar]. Importantly, stress perception and its downstream responses should be considered as context-dependent, and are influenced by the stress type, severity, and duration. Nevertheless, an integral aspect of stress is the accumulation of unfolded or misfolded proteins (i.e., proteotoxic stress) [5.Liu J. Howell S.H. Endoplasmic reticulum protein quality control and its relationship to environmental stress responses in plants.Plant Cell. 2010; 22: 2930-2942Crossref PubMed Scopus (292) Google Scholar]. The ER is essential for protein folding and secretion and has different mechanisms for protein quality control (QC). However, once the amount of unfolded or misfolded proteins surpasses the level that can be controlled by the ERQC, cells have to cope with the cytotoxicity of hampered proteostasis, called ER stress. This also occurs in chloroplasts and mitochondria [6.Dogra V. et al.Impaired PSII proteostasis triggers a UPR-like response in the var2 mutant of Arabidopsis.J. Exp. Bot. 2019; 70: 3075-3088Crossref PubMed Scopus (22) Google Scholar,7.Wang X. Auwerx J. Systems phytohormone responses to mitochondrial proteotoxic stress.Mol. Cell. 2017; 68: 540-551Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Restoration of organellar proteostasis requires responses from both the organelle and the nucleus, and depends on intricate crosstalk between subcellular compartments. Hence, a tight communication established via anterograde and retrograde signaling is necessary for coordinated gene expression to restore proteostasis (Box 1). Eukaryotes rely on the evolutionary conserved retrograde signaling pathway called the UPR, that initiates a series of transcriptional and translational changes to restore the balance between folding capacity and demand [8.Liu J. Howell S.H. Managing the protein folding demands in the endoplasmic reticulum of plants.New Phytol. 2016; 211: 418-428Crossref PubMed Scopus (85) Google Scholar]. Though UPR is well described in mammals, the basic machinery present in plants has been discovered only recently. Increasing evidence underscores emerging roles for plant hormones, [e.g., salicylic acid (SA) [9.Poór P. et al.The multifaceted roles of plant hormone salicylic acid in endoplasmic reticulum stress and unfolded protein response.Int. J. Mol. Sci. 2019; 20: 5842Crossref Scopus (10) Google Scholar], jasmonic acid (JA) [7.Wang X. Auwerx J. Systems phytohormone responses to mitochondrial proteotoxic stress.Mol. Cell. 2017; 68: 540-551Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar], auxin, and ETH [7.Wang X. Auwerx J. Systems phytohormone responses to mitochondrial proteotoxic stress.Mol. Cell. 2017; 68: 540-551Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,10.Chen Y. et al.Inter-regulation of the unfolded protein response and auxin signaling.Plant J. 2014; 77: 97-107Crossref PubMed Scopus (31) Google Scholar]], secondary messengers (e.g., Ca2+) [11.Wilkins K. et al.Calcium-mediated abiotic stress signaling in roots.Front. Plant Sci. 2016; 7: 1296Crossref PubMed Scopus (71) Google Scholar], as well as other signaling molecules such as ROS and sugars, as important regulators of the plant UPR. The well-established intimate relationship between ROS and ETH as key mediators of general stress responses, and their connection to sugar signaling prompts a reassessment of their coordinate involvement in UPR. We believe that there is significant evidence for such connections, and propose that this triad acts at the crossroads of proteotoxic stress and energy signaling. Though it is certain that other molecular players (e.g., SA, auxin, and Ca2+) are important drivers of UPR as well, these will not be discussed within the frame of this work.Box 1Organellar Stress Responses Require Anterograde and Retrograde Signaling CascadesStress sensing and response can occur at the plasma membrane and in different organelles, including the endoplasmic reticulum (ER), mitochondria, and chloroplasts [67.Zhu J. Abiotic stress signaling and responses in plants.Cell. 2016; 167: 313-324Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar]. For instance, stress signals can disrupt electron transport chains, causing ROS accumulation, severe metabolic imbalances, and disturbed proteostasis [38.Choudhury F.K. et al.Reactive oxygen species, abiotic stress, and stress combination.Plant J. 2016; 90: 856-867Crossref PubMed Scopus (772) Google Scholar]. Integration of signals emerging from subcellular compartments is especially relevant for mitochondria and chloroplasts, given their endosymbiont origin. Over the course of evolution, these organelles have become semi-autonomous due to the large number of 'organellar' functions now encoded on the nuclear genome. Consequently, their development and performance depend on intricate communication with the nucleus. Anterograde (nucleus-to-organelle) and retrograde (organelle-to-nucleus) signaling routes are indispensable to steer nuclear expression of organelle-localized proteins in adaptation to stress (Figure I). In chloroplasts, stress-induced ROS production causes the accumulation of several retrograde signals, including carotenoid derivatives, the isoprenoid precursor methylerythritol cyclodiphosphate (MEcPP), and 3′-phosphoadenosine-5′-phosphate (PAP), leading to the induction of 'stress genes' in the nucleus (Figure I) [2.Chan K.X. et al.Learning the languages of the chloroplast: retrograde signaling and beyond.Annu. Rev. Plant Biol. 2016; 67: 25-53Crossref PubMed Scopus (262) Google Scholar]. The pentatricopeptide repeat (PPR) protein GENOMES UNCOUPLED 1 (GUN1), another well-known retrograde signaling component, was recently shown to be involved in plastidial proteostasis [4.Wu G. et al.Control of retrograde signalling by protein import and cytosolic folding stress.Nat. Plants. 2019; 5: 525-538Crossref PubMed Scopus (46) Google Scholar]. Upon environmental stress, GUN1 functioning is associated with improved protein import and reduced accumulation of unfolded plastid proteins in the cytosol. In mitochondria, ROS, PAP, and other unknown signals act as retrograde signals (Figure I), though a well-defined mechanistic understanding of these pathways is lacking. Ng et al. (2013) demonstrated that mitochondrial stress activates the proteolytic cleavage of the ER-bound ANAC017 transcription factor. ANAC017 is essential for the nuclear induction of ALTERNATIVE OXIDASE 1a (AOX1a) [68.Ng S. et al.A membrane-bound NAC transcription factor, ANAC017, mediates mitochondrial retrograde signaling in Arabidopsis.Plant Cell. 2013; 25: 3450-3471Crossref PubMed Scopus (190) Google Scholar], an important marker for mitochondrial retrograde regulation, supporting metabolic homeostasis by avoiding over-reduction of ubiquinone (Figure I). This mechanism illustrates the importance of inter-organelle communication under stress, in addition to canonical retrograde signaling. Other examples include the role of MEcPP in ER stress [69.Benn G. et al.Plastidial metabolite MEcPP induces a transcriptionally centered stress-response hub via the transcription factor CAMTA3.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 8855-8860Crossref PubMed Scopus (33) Google Scholar], or the presence of PAP in different subcellular compartments [70.Van Aken O. Pogson B.J. Convergence of mitochondrial and chloroplastic ANAC017/PAP-dependent retrograde signalling pathways and suppression of programmed cell death.Cell Death Differ. 2017; 24: 955-960Crossref PubMed Scopus (32) Google Scholar]. The exchange of these signaling molecules can even be further facilitated by the presence of membrane contact sites (MCS) between the ER and other organelles (Figure I) [71.Wu H. et al.Here, there and everywhere: the importance of ER membrane contact sites.Science. 2018; 361eaan5835Crossref PubMed Scopus (199) Google Scholar]. Altogether, it is clear that plants have evolved an intricate inter-organelle signaling network to respond to stress. Stress sensing and response can occur at the plasma membrane and in different organelles, including the endoplasmic reticulum (ER), mitochondria, and chloroplasts [67.Zhu J. Abiotic stress signaling and responses in plants.Cell. 2016; 167: 313-324Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar]. For instance, stress signals can disrupt electron transport chains, causing ROS accumulation, severe metabolic imbalances, and disturbed proteostasis [38.Choudhury F.K. et al.Reactive oxygen species, abiotic stress, and stress combination.Plant J. 2016; 90: 856-867Crossref PubMed Scopus (772) Google Scholar]. Integration of signals emerging from subcellular compartments is especially relevant for mitochondria and chloroplasts, given their endosymbiont origin. Over the course of evolution, these organelles have become semi-autonomous due to the large number of 'organellar' functions now encoded on the nuclear genome. Consequently, their development and performance depend on intricate communication with the nucleus. Anterograde (nucleus-to-organelle) and retrograde (organelle-to-nucleus) signaling routes are indispensable to steer nuclear expression of organelle-localized proteins in adaptation to stress (Figure I). In chloroplasts, stress-induced ROS production causes the accumulation of several retrograde signals, including carotenoid derivatives, the isoprenoid precursor methylerythritol cyclodiphosphate (MEcPP), and 3′-phosphoadenosine-5′-phosphate (PAP), leading to the induction of 'stress genes' in the nucleus (Figure I) [2.Chan K.X. et al.Learning the languages of the chloroplast: retrograde signaling and beyond.Annu. Rev. Plant Biol. 2016; 67: 25-53Crossref PubMed Scopus (262) Google Scholar]. The pentatricopeptide repeat (PPR) protein GENOMES UNCOUPLED 1 (GUN1), another well-known retrograde signaling component, was recently shown to be involved in plastidial proteostasis [4.Wu G. et al.Control of retrograde signalling by protein import and cytosolic folding stress.Nat. Plants. 2019; 5: 525-538Crossref PubMed Scopus (46) Google Scholar]. Upon environmental stress, GUN1 functioning is associated with improved protein import and reduced accumulation of unfolded plastid proteins in the cytosol. In mitochondria, ROS, PAP, and other unknown signals act as retrograde signals (Figure I), though a well-defined mechanistic understanding of these pathways is lacking. Ng et al. (2013) demonstrated that mitochondrial stress activates the proteolytic cleavage of the ER-bound ANAC017 transcription factor. ANAC017 is essential for the nuclear induction of ALTERNATIVE OXIDASE 1a (AOX1a) [68.Ng S. et al.A membrane-bound NAC transcription factor, ANAC017, mediates mitochondrial retrograde signaling in Arabidopsis.Plant Cell. 2013; 25: 3450-3471Crossref PubMed Scopus (190) Google Scholar], an important marker for mitochondrial retrograde regulation, supporting metabolic homeostasis by avoiding over-reduction of ubiquinone (Figure I). This mechanism illustrates the importance of inter-organelle communication under stress, in addition to canonical retrograde signaling. Other examples include the role of MEcPP in ER stress [69.Benn G. et al.Plastidial metabolite MEcPP induces a transcriptionally centered stress-response hub via the transcription factor CAMTA3.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 8855-8860Crossref PubMed Scopus (33) Google Scholar], or the presence of PAP in different subcellular compartments [70.Van Aken O. Pogson B.J. Convergence of mitochondrial and chloroplastic ANAC017/PAP-dependent retrograde signalling pathways and suppression of programmed cell death.Cell Death Differ. 2017; 24: 955-960Crossref PubMed Scopus (32) Google Scholar]. The exchange of these signaling molecules can even be further facilitated by the presence of membrane contact sites (MCS) between the ER and other organelles (Figure I) [71.Wu H. et al.Here, there and everywhere: the importance of ER membrane contact sites.Science. 2018; 361eaan5835Crossref PubMed Scopus (199) Google Scholar]. Altogether, it is clear that plants have evolved an intricate inter-organelle signaling network to respond to stress. Upon accumulation of unfolded or misfolded proteins in the ER, cells trigger UPR to mitigate ER stress. This intracellular signaling mechanism aims to restore protein homeostasis by upregulating genes involved in protein folding and ER-associated degradation (ERAD), or by induction of autophagy (Figure 1B) [8.Liu J. Howell S.H. Managing the protein folding demands in the endoplasmic reticulum of plants.New Phytol. 2016; 211: 418-428Crossref PubMed Scopus (85) Google Scholar]. If ER stress persists, UPR signaling further induces the expression of autophagy-related genes, but ultimately resorts to programmed cell death (PCD) (Figure 1C) [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,13.Srivastava R. et al.Response to persistent ER stress in plants: a multiphasic process that transitions cells from prosurvival activities to cell death.Plant Cell. 2018; 30: 1220-1242Crossref PubMed Scopus (32) Google Scholar]. In mammalians, UPR plays a key role in many diseases characterized by chronic ER stress [14.Hetz C. et al.Proteostasis control by the unfolded protein response.Nat. Cell Biol. 2015; 17: 829-838Crossref PubMed Scopus (369) Google Scholar]. In plants, UPR mitigates ER stress caused by a wide range of (a)biotic stresses overwhelming the protein folding machinery [15.Park C. Park J.M. Endoplasmic reticulum plays a critical role in integrating signals generated by both biotic and abiotic stress in plants.Front. Plant Sci. 2019; 10: 399Crossref PubMed Scopus (25) Google Scholar]. Although UPR is conserved among eukaryotes, some signaling components differ between kingdoms. In metazoans, UPR consists of three branches regulated by inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK). By contrast, the plant UPR comprises two branches (Box 2) [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. The first is regulated by IRE1, which induces the unconventional splicing of the BASIC LEUCINE ZIPPER 60 (bZIP60) transcription factor. The second branch relies on the transcription factors bZIP17 and bZIP28, representing ATF6 homologs. A PERK homolog has not been identified in plants [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Interestingly, spliced bZIP60 is able to move from cell to cell through plasmodesmata (PD), mainly from root to shoot, supporting its involvement in non-cell autonomous, systemic UPR signaling, besides its role in local, intracellular responses to ER stress [16.Lai Y.-.S. et al.Systemic signaling contributes to the unfolded protein response of the plant endoplasmic reticulum.Nat. Commun. 2018; 9: 3918Crossref PubMed Scopus (12) Google Scholar].Box 2Basic UPR Machinery in PlantsThe core unfolded protein response (UPR) machinery has been mainly characterized in arabidopsis. It relies on three transcription factors belonging to the basic leucine zipper (bZIP) family and consists of two main branches (Figure I). The first is the most conserved in eukaryotes and is regulated by inositol-requiring enzyme 1 (IRE1). This transmembrane protein contains an endoplasmic reticulum (ER)-luminal protein–protein interaction domain and a cytosolic tail with kinase and RNase domains. In response to ER stress, IRE1 homodimerizes and trans-autophosphorylates its kinase domain [72.Koizumi N. et al.Molecular characterization of two Arabidopsis Ire1 homologs, endoplasmic reticulum-located transmembrane protein kinases.Plant Physiol. 2001; 127: 949-962Crossref PubMed Scopus (177) Google Scholar]. The resulting conformational change activates the RNase domain that subsequently catalyzes unconventional splicing of bZIP60 in a process termed regulated IRE-dependent splicing (RIDS). This causes a frameshift removing the ER anchor, which allows translocation of the activated bZIP60 to the nucleus, inducing the expression of ER stress-responsive genes [8.Liu J. Howell S.H. Managing the protein folding demands in the endoplasmic reticulum of plants.New Phytol. 2016; 211: 418-428Crossref PubMed Scopus (85) Google Scholar,73.Nagashima Y. et al.Arabidopsis IRE1 catalyses unconventional splicing of bZIP60 mRNA to produce the active transcription factor.Sci. Rep. 2011; 1: 29Crossref PubMed Scopus (198) Google Scholar]. IRE1 also engages in cleavage and bulk degradation of specific mRNAs during regulated IRE-dependent decay (RIDD). This process might relieve ER stress by degrading mRNAs encoding ER-resident proteins, thereby decreasing the protein folding load [74.Mishiba K. et al.Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 5713-5718Crossref PubMed Scopus (103) Google Scholar]. Alternatively, RIDD can guide cells toward autophagy by eliminating mRNAs encoding negative regulators of this process [75.Bao Y. et al.IRE1B degrades RNAs encoding proteins that interfere with the induction of autophagy by ER stress in Arabidopsis thaliana.Autophagy. 2018; 14: 1562-1573Crossref PubMed Scopus (33) Google Scholar].The main players of the second UPR branch are the bZIP17 and bZIP28 transcription factors (Figure I). These transmembrane proteins contain a cytosolic N-terminal part harboring a transcription factor domain and a C-terminal part residing in the ER lumen. Under unstressed conditions, bZIP28 is retained in the ER due to binding of its C-terminal domain to the ER chaperone binding protein (BiP). Upon perceiving ER stress, BiP binds to unfolded proteins to prevent their aggregation, causing bZIP28 dissociation and translocation to the Golgi [76.Liu J. et al.An endoplasmic reticulum stress response in Arabidopsis is mediated by proteolytic processing and nuclear relocation of a membrane-associated transcription factor, bZIP28.Plant Cell. 2007; 19: 4111-4119Crossref PubMed Scopus (290) Google Scholar,77.Srivastava R. et al.Binding Protein is a master regulator of the endoplasmic reticulum stress sensor/transducer bZIP28 in Arabidopsis.Plant Cell. 2013; 25: 1416-1429Crossref PubMed Scopus (92) Google Scholar]. Here, regulated intermembrane proteolysis by proteases releases the active bZIP28 transcription factor domain into the cytosol, enabling its nuclear translocation [78.Iwata Y. et al.Activation of the Arabidopsis membrane-bound transcription factor bZIP28 is mediated by site-2 protease, but not site-1 protease.Plant J. 2017; 91: 408-415Crossref PubMed Scopus (32) Google Scholar]. Although the activation mechanism of bZIP17 might be similar, the interacting protein responsible for its retention in the ER under nonstressed conditions is currently unknown [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar].In the nucleus, bZIP28 and bZIP60 bind to conserved ER stress response element (ERSE) and unfolded protein response element (UPRE) cis-regulatory motifs in the promoter region of ER stress-responsive genes to regulate their expression [8.Liu J. Howell S.H. Managing the protein folding demands in the endoplasmic reticulum of plants.New Phytol. 2016; 211: 418-428Crossref PubMed Scopus (85) Google Scholar]. For a comprehensive overview of the UPR machinery in plants and its comparison to that in other eukaryotes, readers are referred to Pastor-Cantizano et al. (2020) [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. The core unfolded protein response (UPR) machinery has been mainly characterized in arabidopsis. It relies on three transcription factors belonging to the basic leucine zipper (bZIP) family and consists of two main branches (Figure I). The first is the most conserved in eukaryotes and is regulated by inositol-requiring enzyme 1 (IRE1). This transmembrane protein contains an endoplasmic reticulum (ER)-luminal protein–protein interaction domain and a cytosolic tail with kinase and RNase domains. In response to ER stress, IRE1 homodimerizes and trans-autophosphorylates its kinase domain [72.Koizumi N. et al.Molecular characterization of two Arabidopsis Ire1 homologs, endoplasmic reticulum-located transmembrane protein kinases.Plant Physiol. 2001; 127: 949-962Crossref PubMed Scopus (177) Google Scholar]. The resulting conformational change activates the RNase domain that subsequently catalyzes unconventional splicing of bZIP60 in a process termed regulated IRE-dependent splicing (RIDS). This causes a frameshift removing the ER anchor, which allows translocation of the activated bZIP60 to the nucleus, inducing the expression of ER stress-responsive genes [8.Liu J. Howell S.H. Managing the protein folding demands in the endoplasmic reticulum of plants.New Phytol. 2016; 211: 418-428Crossref PubMed Scopus (85) Google Scholar,73.Nagashima Y. et al.Arabidopsis IRE1 catalyses unconventional splicing of bZIP60 mRNA to produce the active transcription factor.Sci. Rep. 2011; 1: 29Crossref PubMed Scopus (198) Google Scholar]. IRE1 also engages in cleavage and bulk degradation of specific mRNAs during regulated IRE-dependent decay (RIDD). This process might relieve ER stress by degrading mRNAs encoding ER-resident proteins, thereby decreasing the protein folding load [74.Mishiba K. et al.Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 5713-5718Crossref PubMed Scopus (103) Google Scholar]. Alternatively, RIDD can guide cells toward autophagy by eliminating mRNAs encoding negative regulators of this process [75.Bao Y. et al.IRE1B degrades RNAs encoding proteins that interfere with the induction of autophagy by ER stress in Arabidopsis thaliana.Autophagy. 2018; 14: 1562-1573Crossref PubMed Scopus (33) Google Scholar]. The main players of the second UPR branch are the bZIP17 and bZIP28 transcription factors (Figure I). These transmembrane proteins contain a cytosolic N-terminal part harboring a transcription factor domain and a C-terminal part residing in the ER lumen. Under unstressed conditions, bZIP28 is retained in the ER due to binding of its C-terminal domain to the ER chaperone binding protein (BiP). Upon perceiving ER stress, BiP binds to unfolded proteins to prevent their aggregation, causing bZIP28 dissociation and translocation to the Golgi [76.Liu J. et al.An endoplasmic reticulum stress response in Arabidopsis is mediated by proteolytic processing and nuclear relocation of a membrane-associated transcription factor, bZIP28.Plant Cell. 2007; 19: 4111-4119Crossref PubMed Scopus (290) Google Scholar,77.Srivastava R. et al.Binding Protein is a master regulator of the endoplasmic reticulum stress sensor/transducer bZIP28 in Arabidopsis.Plant Cell. 2013; 25: 1416-1429Crossref PubMed Scopus (92) Google Scholar]. Here, regulated intermembrane proteolysis by proteases releases the active bZIP28 transcription factor domain into the cytosol, enabling its nuclear translocation [78.Iwata Y. et al.Activation of the Arabidopsis membrane-bound transcription factor bZIP28 is mediated by site-2 protease, but not site-1 protease.Plant J. 2017; 91: 408-415Crossref PubMed Scopus (32) Google Scholar]. Although the activation mechanism of bZIP17 might be similar, the interacting protein responsible for its retention in the ER under nonstressed conditions is currently unknown [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. In the nucleus, bZIP28 and bZIP60 bind to conserved ER stress response element (ERSE) and unfolded protein response element (UPRE) cis-regulatory motifs in the promoter region of ER stress-responsive genes to regulate their expression [8.Liu J. Howell S.H. Managing the protein folding demands in the endoplasmic reticulum of plants.New Phytol. 2016; 211: 418-428Crossref PubMed Scopus (85) Google Scholar]. For a comprehensive overview of the UPR machinery in plants and its comparison to that in other eukaryotes, readers are referred to Pastor-Cantizano et al. (2020) [12.Pastor-Cantizano N. et al.Functional diversification of ER stress responses in Arabidopsis.Trends Biochem. Sci. 2020; 45: 123-136Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. The plant UPR is best characterized in response to ER stress (erUPR); however, impairment of proteostasis in other subcellular compartments (Box 1) appears to activate similar signaling mechanisms. Dogra et al. (2019) showed the presence of a UPR-like response in chloroplasts of the arabidopsis (Arabidopsis thaliana) yellow leaf variegation 2 (var2) mutant, that accumulates damaged photosystem II proteins [6.Dogra V. et al.Impaired PSII proteostasis triggers a UPR-like response in the var2 mutant of Arabidopsis.J. Exp. Bot. 2019; 70: 3075-3088Crossref PubMed Scopus (22) Google Scholar]. Defects in Clp protease activity were also shown to induce a plastidial UPR (cpUPR) [17.Llamas E. et al.Interference with plastome gene expression and Clp protease activity in Arabid