Homeostasis of the endoplasmic reticulum (ER) is critical for growth, development, and stress responses. Perturbations causing an imbalance in ER proteostasis lead to a potentially lethal condition known as ER stress. In ER stress situations, cell-fate decisions either activate pro-life pathways that reestablish homeostasis or initiate pro-death pathways to prevent further damage to the organism. Understanding the mechanisms underpinning cell-fate decisions in ER stress is critical for crop development and has the potential to enable translation of conserved components to ER stress-related diseases in metazoans. Post-translational modifications (PTMs) of proteins are emerging as key players in cell-fate decisions in situations of imbalanced ER proteostasis. In this review, we address PTMs orchestrating cell-fate decisions in ER stress in plants and provide evidence-based perspectives for where future studies may focus to identify additional PTMs involved in ER stress management.

The endoplasmic reticulum (ER) performs myriad cellular functions, like synthesizing one-third of the cell's proteome, lipid biosynthesis, and initiating glycosylation of secretory proteins. A healthy and properly functioning ER is therefore paramount for growth, development, and response to the environment. Perturbations to the cellular environment can elicit ER stress where the ER capacity to fold proteins is exceeded. This condition is linked to numerous pathologies in humans and crop losses in plants [1–7]. Cells respond to ER stress through conserved mechanisms including, but not limited to, the unfolded protein response (UPR), ER-associated degradation (ERAD), ER-phagy, and aggrephagy [1,2,8]. The UPR is conserved across eukaryotes [9] and functions to restore homeostasis when ER stress can be resolved or induce cell death when the ER stress remains unresolved [10,11]. Metazoans have three main UPR branches led by inositol requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and PKR-like ER kinase (PERK). These proteins sense the accumulation of misfolded proteins in the ER and initiate downstream signaling. In model plant species like Arabidopsis thaliana, the IRE1 and ATF6 branches are conserved as IRE1a, IRE1b, and IRE1c, and basic-leucine zipper 28 (bZIP28), respectively [9,12,13]. General control nonderepressible 2 may represent a homologous branch of the metazoan PERK in plants [14,15], but further elucidation is needed. Furthermore, bZIP17 has been implicated in the UPR during physiological development and salt stress but seems otherwise dispensable in the broad regulation of UPR gene expression [16–18]. Upon sensing ER stress, IRE1, an ER type I membrane-anchored protein, dimerizes and autophosphorylates, activating its ribonuclease domain to unconventionally splice bZIP60 mRNA in the cytoplasm. Spliced bZIP60 encodes a transcription factor (TF) that translocates to the nucleus to modulate UPR gene expression. In ER stress, bZIP28 translocates to the Golgi apparatus and is proteolytically cleaved to release a TF that moves to the nucleus and regulates UPR genes [9,19]. Individually, together, and with other TFs and transcriptional regulators, bZIP60 and bZIP28 control expression of UPR genes, like molecular chaperones that support the ER folding capacity and ERAD components that remove and degrade misfolded proteins from the ER [2,19]. Additionally, IRE1 ribonuclease domain degrades mRNAs globally and selectively [1,20] influencing pathways like autophagy in plants [21]. Cells also respond to ER stress through ERAD, ER-phagy, and aggrephagy, to degrade terminally misfolded proteins, portions of the ER, and toxic protein aggregates, respectively [2,8,22,23]. Despite our current understanding of the ER stress response in plants, the mechanisms surrounding the cell's shift from promoting life to promoting death pathways in unresolved ER stress remains obscure [11].

Although proteins and their proteoforms ultimately yield phenotypes from the cellular to organismal level [24], studies of ER stress responses in plants predominantly focus on transcriptional shifts [25–31] with limited attention given to the post-translational landscape. As gene expression often does not correlate with functional outputs, understanding cellular responses to ER stress requires knowledge of what proteins and proteoforms are present and in what quantity [32,33]. By providing extensive opportunities for functional diversification [24,34] (Figure 1), proteins play critical roles in cell and organismal health and fate [35], which is particularly relevant for the UPR [10,11]. Additionally, post-translational regulation is important in stress conditions by enabling prompt responses to external stimuli [10,11,35]. The Human Proteoform Project highlights the growing importance of post-translational modifications (PTMs), emerging as an imperative area of study [24]. With advancements in protein chemical biology [36] and protein nanopore sequencing technology [37–40] (Figure 2), investigations into proteoforms are bound to become increasingly prominent for enhancing the understanding of ER stress response mechanisms.

Proteoforms produce extensive functional diversity.

Figure 1.
Proteoforms produce extensive functional diversity.

Gene expression encapsulates the progression from DNA to RNA to Protein and co-ordinately expands functional diversity. Any one gene can encode multiple mRNAs with alternative splicing and produce varying levels of each transcript. Each of those unique transcripts can then be translated, at varying levels, into a protein which can undergo extensive modifications to yield proteoforms that perform different functions within the cell. Created with BioRender.com.

Figure 1.
Proteoforms produce extensive functional diversity.

Gene expression encapsulates the progression from DNA to RNA to Protein and co-ordinately expands functional diversity. Any one gene can encode multiple mRNAs with alternative splicing and produce varying levels of each transcript. Each of those unique transcripts can then be translated, at varying levels, into a protein which can undergo extensive modifications to yield proteoforms that perform different functions within the cell. Created with BioRender.com.

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Technological advancements in molecular biology facilitate the capture of functional diversity within the cell.

Figure 2.
Technological advancements in molecular biology facilitate the capture of functional diversity within the cell.

Sanger sequencing, developed in the 1970s, allowed researchers to sequence genes and build genomes to obtain some of the first genetic material. Illumina and Oxford Nanopore sequencing facilitate high-throughput DNA and RNA sequencing, expanding the detectable molecular diversity. Current, cutting-edge research on single protein sequencing will provide the most comprehensive understanding of functional diversity in the cell allowing the identification and quantification of proteoforms. Created with BioRender.com.

Figure 2.
Technological advancements in molecular biology facilitate the capture of functional diversity within the cell.

Sanger sequencing, developed in the 1970s, allowed researchers to sequence genes and build genomes to obtain some of the first genetic material. Illumina and Oxford Nanopore sequencing facilitate high-throughput DNA and RNA sequencing, expanding the detectable molecular diversity. Current, cutting-edge research on single protein sequencing will provide the most comprehensive understanding of functional diversity in the cell allowing the identification and quantification of proteoforms. Created with BioRender.com.

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This review draws attention to the exciting area of PTM research in the plant UPR. We highlight PTMs that influence cell-fate decisions induced by ER stress within the model plant species A. thaliana, and because ER stress is a common plight to eukaryotes, we also highlight PTMs in other organisms, which may represent yet undiscovered layers of protein regulation in cell-fate decisions in plants.

Over 400 PTMs have been identified to date [41], but in this review, we focus on those with prominent roles in cell-fate decisions during ER stress, including proteolysis, phosphorylation, ubiquitination, and ubiquitin-like (UBL) modifications (Figure 3). Other PTMs implicated in the cell's response to ER stress include glycosylation [42,43], persulfidation [44–50], glutathionylation [51,52], nitrosylation [53], acetylation [54–58], arginylation [59–61], and O-GlcNAcylation [62–69].

Post-translational modifications influence ER stress-induced cell-fate decisions.

Figure 3.
Post-translational modifications influence ER stress-induced cell-fate decisions.

Proteolysis, phosphorylation, and ubiquitination and ubiquitin-like (UBL) modifications are critical orchestrators of cell-fate decisions in ER stress conditions. Proteolysis can be digestive, via the 26S proteasomal degradation of proteins into their constituent amino acids or limited which is mediated by a protease to yield gain-of- or switch-of function proteoforms. Phosphorylation is the addition of a phosphate from a donor such as ATP or GTP (represented as XTP) via a kinase to a target protein, which can be removed by the enzymatic activity of phosphatases. Ubiquitin and UBL modifications, including SUMOylation and UFMylation, utilize similar mechanisms for the modification of peptides. In an ATP dependent manner, the modifier is loaded onto an E1 activating protein, transferred to an E2 conjugating protein, and then through an E3 ligase, selects the target protein and transfers the modification. All three modifications are reversible through the action of a protease, and ubiquitination has an E4 chain elongation protein that can build long chains of ubiquitin onto the target protein. Created with BioRender.com.

Figure 3.
Post-translational modifications influence ER stress-induced cell-fate decisions.

Proteolysis, phosphorylation, and ubiquitination and ubiquitin-like (UBL) modifications are critical orchestrators of cell-fate decisions in ER stress conditions. Proteolysis can be digestive, via the 26S proteasomal degradation of proteins into their constituent amino acids or limited which is mediated by a protease to yield gain-of- or switch-of function proteoforms. Phosphorylation is the addition of a phosphate from a donor such as ATP or GTP (represented as XTP) via a kinase to a target protein, which can be removed by the enzymatic activity of phosphatases. Ubiquitin and UBL modifications, including SUMOylation and UFMylation, utilize similar mechanisms for the modification of peptides. In an ATP dependent manner, the modifier is loaded onto an E1 activating protein, transferred to an E2 conjugating protein, and then through an E3 ligase, selects the target protein and transfers the modification. All three modifications are reversible through the action of a protease, and ubiquitination has an E4 chain elongation protein that can build long chains of ubiquitin onto the target protein. Created with BioRender.com.

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Contrary to PTMs that covalently attach molecules to proteins, proteolysis hydrolyzes proteins into amino acids or smaller polypeptides/proteoforms. Digestive proteolysis, like the ubiquitin-proteasome system (UPS), involves terminal degradation and protein recycling. Limited proteolysis, a PTM, expands the proteome by producing gain-of- or switch-of-function proteoforms [70] (Figure 3). Proteolysis, playing diverse roles, is crucial for development [70,71], with emerging relevance for ER stress. Current understanding of limited proteolysis via regulated intramembrane proteolysis (RIP) in ER stress suggests a role as a signal transduction mechanism for rapid responses to cellular state changes. The ER membrane proteins bZIP17 and bZIP28 respond to salt stress and ER stress, respectively, and translocate from the ER to the Golgi, where RIP releases the cytosolic N-terminal transcriptional activation domains that translocate to the nucleus as active TFs [18,72]. Being cleaved by the site-1 protease (S1P) then site-2 protease (S2P) for release from the Golgi, bZIP17 resembles ATF6 [73]; while despite bZIP28 containing an S1P recognition motif, its cleavage is observed in an s1p knockout mutant, but not an s2p mutant [18,74] suggesting there is more to be understood about the mechanism of bZIP28 proteolysis-driven activation. Active bZIP28 has a well-established role in promoting gene expression that supports ER proteostasis and cell survival [75], while bZIP17, which interacts with both bZIP28 and bZIP60 in yeast, seems to have a limited role in comparison [16]. Therefore, proteolytic processing and activation of the ER membrane-anchored bZIP28 protein is critical to homeostasis and growth under ER stress conditions.

Another ER membrane-anchored protein, B-cell lymphoma (Bcl-2)-associated athanogene 7 (BAG7), has been implicated in the UPR through a combination of abiotic stresses that induce ER stress, and chemical induction via tunicamycin. Upon ER stress, BAG7 is proteolytically cleaved via an unknown protease, releasing a TF into the cytosol that moves to the nucleus to regulate gene expression [76,77]. Knockout of BAG7 leads to increased sensitivity to ER stress and death. BAG7 cytoprotective role is dependent on its proteolytic cleavage and translocation to the nucleus as well as its SUMOylation [77], highlighting the combinatorial nature of PTMs in regulating cell-fate decisions in stress.

Membrane-tethered TFs in the NAC family also play significant roles in ER stress induced cell-fate decisions. NAC with Transmembrane motif 1-Like 7 (NTL7) is proteolytically cleaved by a rhomboid protease in ER stress, releasing a TF that translocates to the nucleus to up-regulate pro-survival genes, including molecular chaperones and bZIP60 [78,79]. The plasma membrane (PM)-localized NTL6 is proteolytically cleaved to produce a TF in response to ER stress that translocates to the nucleus [80,81]. NTL6 cleavage is independent of S1P, but its RIP is partially suppressed by a metalloprotease inhibitor suggesting a different protease may be responsible for its activation [81,82]. In the nucleus, NTL6 binds the promoters of pro-survival chaperones to up-regulate their expression, and a ntl6 mutant is hypersensitive to ER stress [80]. Finally, NTL14 (ANAC089) is an ER membrane-bound TF that in ER stress is activated and translocates to the nucleus to up-regulate programmed cell-death related genes; however the activation mechanisms are currently unknown [10]. These examples highlight that RIP is critical to ER stress responses in plants but also that the underlying mechanisms are yet to be discovered (Figure 4).

PTM of transcription factors regulate life or death pathways in ER stress.

Figure 4.
PTM of transcription factors regulate life or death pathways in ER stress.

A diagram of a plant cell where red arrows depict molecular occurrences in response to ER stress. In conditions of ER stress, proteolytic cleavage releases the TFs bZIP28, BAG7, NTL6, NTL7, and NTL14 from their membrane bound state for transport into the nucleus. BAG7 also undergoes SUMOylation for its activation. NTL6, NTL7, and BAG7 all promote pro-life gene expression, while NTL14 promotes pro-death gene expression. COP1, a ubiquitin E3 ligase, also translocates to the nucleus in response to ER stress where it ubiquitinates HY5 for degradation, removing its suppression of pro-life genes in ER stress for bZIP28 to bind and drive their expression. Additionally, PIR1, also a ubiquitin E3 ligase, in unresolved ER stress indirectly drives UPS degradation of ABI5, a TF that drives pro-life gene expression. Created with BioRender.com.

Figure 4.
PTM of transcription factors regulate life or death pathways in ER stress.

A diagram of a plant cell where red arrows depict molecular occurrences in response to ER stress. In conditions of ER stress, proteolytic cleavage releases the TFs bZIP28, BAG7, NTL6, NTL7, and NTL14 from their membrane bound state for transport into the nucleus. BAG7 also undergoes SUMOylation for its activation. NTL6, NTL7, and BAG7 all promote pro-life gene expression, while NTL14 promotes pro-death gene expression. COP1, a ubiquitin E3 ligase, also translocates to the nucleus in response to ER stress where it ubiquitinates HY5 for degradation, removing its suppression of pro-life genes in ER stress for bZIP28 to bind and drive their expression. Additionally, PIR1, also a ubiquitin E3 ligase, in unresolved ER stress indirectly drives UPS degradation of ABI5, a TF that drives pro-life gene expression. Created with BioRender.com.

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Protein phosphorylation is essential for stress responses, signaling, and development [6,35,83]. It involves adding a phosphate group to a serine, threonine, or tyrosine residue of a peptide. Facilitated by kinases and reversible by phosphatases, this process, can impact various protein attributes [83] (Figure 3). While human, mice, and yeast have 230 000, 156 000, and 40 000 estimated phosphosites, respectively, most phosphosites in A. thaliana remain undiscovered [84], highlighting the potential for investigating phosphorylation directing plant cell-fate during ER stress [35]. Indeed, an up-regulation of genes encoding kinases in Solanum tuberosum [85] and an increased abundance of kinases and 14-3-3 proteins in rice seeds [86] during ER stress suggests a participation of phosphorylation events. Despite these observations, a molecular characterization of ER stress-induced phosphorylation changes in plants is lacking. Studies in other species have shown that phosphorylation events influence cell-fate during ER stress responses; for instance, the CDK5-MEKK1-JNK(MAPK) kinase cascade in ER-stressed mouse cells signals apoptosis [87], and tyrosine kinase cascades in human cells during ER stress trigger the relocation of TFs to the nucleus to promote adaptive ER stress responses [88]. Therefore, future phosphoproteomics with functional characterizations in ER stress conditions in plants may unveil how phosphorylation networks guide cell-fate decisions.

IRE1 activation requires phosphorylation [9] (Figure 5A). While the molecular details of IRE1 activation in plants are relatively undefined, findings in other eukaryotes provide insights into putative mechanisms of phosphorylation-dependent regulation of this most ancient and highly conserved branch of the UPR. For example, abrogation of the murine IRE1 autophosphorylation site S724 prevents complete autophosphorylation and depresses its RNase activity, leading to heightened ER stress levels [89]. Furthermore, in mouse hepatocytes, that same site, S724, is phosphorylated by the kinase PKA in response to hormone signaling [90], suggesting that IRE1 phosphorylation may be a convergence point for the regulation of IRE1 activity and downstream signaling to transduce different signals spatially, temporally, and in different conditions. The S724 site is conserved in A. thaliana IRE1a and IRE1c, but is an alanine in IRE1b; however, all three IRE1 proteins encode an extra serine at the preceding residue, which is not present in murine IRE1 (Figure 6). Therefore, future studies may benefit from analyses with single and combinatorial IRE1 phosphomutants to evaluate if and how phosphorylation modulates the function of IRE1 in plant cells.

PTMs at the ER membrane regulate cytoplasmic responses that direct cell-fate in ER stress.

Figure 5.
PTMs at the ER membrane regulate cytoplasmic responses that direct cell-fate in ER stress.

A diagram of a plant cell where red arrows depict molecular occurrences in response to ER stress. (A) IRE1, an ancestral and major branch of the UPR that orchestrates many downstream pathways in response to ER stress, is activated via autophosphorylation. (B) ERAD, also a pro-life mechanism in ER stress, relies on ubiquitination to regulate its activity and target its cargo (misfolded proteins) for proteasomal degradation. Auto- and trans-ubiquitination subdue ERAD activity in physiological conditions, but in response to ER stress, this ubiquitination is suppressed to increase ERAD throughput. (C) ER-phagy, a pro-life mechanism in ER stress, utilizes UFMylation and its machinery. Created with BioRender.com.

Figure 5.
PTMs at the ER membrane regulate cytoplasmic responses that direct cell-fate in ER stress.

A diagram of a plant cell where red arrows depict molecular occurrences in response to ER stress. (A) IRE1, an ancestral and major branch of the UPR that orchestrates many downstream pathways in response to ER stress, is activated via autophosphorylation. (B) ERAD, also a pro-life mechanism in ER stress, relies on ubiquitination to regulate its activity and target its cargo (misfolded proteins) for proteasomal degradation. Auto- and trans-ubiquitination subdue ERAD activity in physiological conditions, but in response to ER stress, this ubiquitination is suppressed to increase ERAD throughput. (C) ER-phagy, a pro-life mechanism in ER stress, utilizes UFMylation and its machinery. Created with BioRender.com.

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Conservation across eukaryotes of modifiable residues.

Figure 6.
Conservation across eukaryotes of modifiable residues.

(A) Alignment with Clustal Omega [177,178] of mouse and A. thaliana IRE1 amino acid sequences. Murine IRE1, S724 is conserved in A. thaliana IRE1a and IRE1c. A. thaliana IRE1b has an alanine at the homologous position but a Serine in the adjacent position. (B) AlphaFold predicted structures [179–181] and alignment with Clustal Omega [177,178] of human, C. reinhardtii, and A. thaliana BiP amino acid sequences. Highlighted is the AMPylation site of the metazoan BiP, the phosphorylation site in C. reinhardtii, and the phosphorylation site in A. thaliana BiP1 and BiP2. Red arrows on the AlphaFold structures denote the modified residue. A. thaliana BiP1 and BiP2 sequences are highly homologous so only BiP1 AlphaFold structure is shown. Created with BioRender.com.

Figure 6.
Conservation across eukaryotes of modifiable residues.

(A) Alignment with Clustal Omega [177,178] of mouse and A. thaliana IRE1 amino acid sequences. Murine IRE1, S724 is conserved in A. thaliana IRE1a and IRE1c. A. thaliana IRE1b has an alanine at the homologous position but a Serine in the adjacent position. (B) AlphaFold predicted structures [179–181] and alignment with Clustal Omega [177,178] of human, C. reinhardtii, and A. thaliana BiP amino acid sequences. Highlighted is the AMPylation site of the metazoan BiP, the phosphorylation site in C. reinhardtii, and the phosphorylation site in A. thaliana BiP1 and BiP2. Red arrows on the AlphaFold structures denote the modified residue. A. thaliana BiP1 and BiP2 sequences are highly homologous so only BiP1 AlphaFold structure is shown. Created with BioRender.com.

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PERK is a critical sensor of the metazoan UPR that phosphorylates eukaryotic initiation factor 2 alpha (eIF2a), which results in general inhibition of translation, but also selective translation of mRNAs that support the UPR [1]. The PERK pathway is additionally enriched with phosphorylation cascades directing cell-fate in response to ER stress [91–97]. Despite the lack of a PERK sequence homologue, the Arabidopsis eIF2a homologue undergoes phosphorylation in response to ER stress [98], suggesting the presence of a PERK-like pathway in plants. Therefore, investigations into the phosphorylation networks surrounding eIF2a in plants may expand the understanding of the role phosphorylation plays in mediating plant ER stress responses.

Critical to ER stress resolution are ER molecular chaperones, which are generally up-regulated in ER stress [99]. In addition to transcriptional up-regulation, PTMs may provide expeditious mechanisms for chaperones to respond to ER stress. In mammalian cells, the well-established ER stress marker and essential chaperone, binding immunoglobulin protein (BiP), is AMPylated/deAMPylated in its substrate binding domain (SBD) by the type II ER membrane protein Filamentation Induced by Cyclic-AMP (FIC) domain containing-protein (FICD) to tune the pool of active BiP proteins with the misfolded protein load [100]. While FICD does not appear to be conserved in plants, Chlamydomonas reinhardtii BiP exhibits a phosphorylation site that responds to ER stress and ER protein load [101]. Phosphorylation at this site may inactivate BiP [101] as supported by the inability of the T520E phosphomimic form of C. reinhardtii BiP to complement the yeast mutant defective in Kar2 (yeast BiP homolog), and the fact that, like the mammalian AMPylation, this PTM also occurs within the C. reinhardtii SBD [101]. Further studies are required for validating this hypothesis, but the homologous site in A. thaliana BiP1 and BiP2 is a serine (Figure 6) and was detected in two different studies to be phosphorylated [102–104], suggesting a regulatory potential for this PTM in land plants. Like BiP, other heat shock proteins (HSPs) are involved in phosphorylation-dependent modulation of downstream cell-fate decisions in mammalian cells including HSP20 [105] and HSPB1 [106]. Finally, phosphorylation of other molecular chaperones also direct cell-fate outcomes. For example, knockdown of protein phosphatase 2A subunit B′γ (PP2A-B′γ), a PP2A subunit with known roles as a negative regulator of immune response in A. thaliana, leads to the hyperphosphorylation of the ER molecular chaperone, calreticulin (CRT1), and correlates with early senescence and cell death [107,108]. Additionally, while mammalian protein disulfide isomerases (PDIs) can be phosphorylated to regulate the ER stress response [109], they can also be UFMylated [110] and SUMOylated to influence ER stress outcomes [111]. There is also evidence of wheat PDI-V being ubiquitinated to influence powdery mildew resistance [112]. These studies support that in ER stress, the function and activity of molecular chaperones can be modulated by PTMs to direct the response to ER stress. Therefore, identification and characterization of PTMs on plant molecular chaperones will be paramount for understanding cell-fate decisions in ER stress in plant cells.

Ubiquitination involves attaching the small 76 amino acid peptide, ubiquitin, to a lysine of a target protein. The process includes an ATP-dependent E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme acting as carrier, and an E3 ubiquitin-protein ligase that transfers ubiquitin to the target protein. E4 chain elongation proteins build ubiquitin chains on target proteins [113], while de-ubiquitinating enzymes (DUBs) remove ubiquitin [114,115]. UBL modifiers like ubiquitin fold modifier-1 (UFM1) and small ubiquitin-related modifier (SUMO) are attached to lysines and share similar mechanisms to ubiquitin, involving E1, E2, and E3 enzymes as well as proteases that cleave off the modification (Figure 3). Despite similarities, UFMylation and SUMOylation do not generally target proteins for the UPS like ubiquitination [116–118]. All of these modifications have been implicated in ER stress response. DUBs and E3 ubiquitin-protein ligases are involved in ER stress-driven cell-fate decisions in mammals [119], and recent studies have highlighted the importance of the UPS in plant ER stress response [86,120]. UFMylation is linked to ER function, stress, and proteostasis in mammalian cells [121], with some conservation in plants [122], and SUMOylation modifies TFs in plants, including those involved in ER stress responses [123]. Despite their crucial roles in ER stress response, the specific mechanisms and components of ubiquitination and UBL modifications in plants are scarcely known, underscoring extensive opportunities for investigations into their involvement in cell-fate decisions.

Numerous examples in metazoa and yeast of ubiquitin and UBL E3 ligases and DUBs orchestrating cell-fate decisions in response to ER stress exist, e.g. PARKIN [124,125], USP5 [126], POSH [127], RNF183 [128], UBE2G2-GP78 [129], USP7 [130], USP19 [131], MuRF1[50] and UBP3-NOT4 [132], but in A. thaliana, the discoveries have been sparse. The E3 ubiquitin-protein ligase PIR1 in A. thaliana is a pro-death factor during unresolved ER stress that indirectly leads to proteasomal degradation of the TF ABA insensitive 5 (ABI5) [120]. In ER stress, ABI5 increases the expression of the critical UPR genes bZIP60 and BiP3 [120] (Figure 4), but beyond ER stress, its function can be modulated by ubiquitin [120,133], phosphorylation [133–136], SUMOylation [137], and their cross-talk [138], suggesting a tight regulation through PTMs. Expanding knowledge on ubiquitin and UBL modifications during ER stress in plants will improve the understanding of how life and death pathways are determined and executed in the cell.

Role of ubiquitination in ERAD

Ubiquitination is central to ERAD, which is a process that relies on proteins associated with the ER that translocate misfolded proteins from the lumen to the cytosol for ubiquitin-dependent UPS degradation [2]. In ER stress, ERAD components are up-regulated as a pro-survival mechanism to manage the increase in terminally misfolded proteins in the ER [2]. E2, E3, E4, and DUB proteins are all utilized by ERAD, and while the understanding of ERAD is much more comprehensive in yeast and humans [139,140] than it is in plants [141], conserved and plant-specific components have been identified. The ER transmembrane protein HRD1 is a critical E3 ubiquitin-protein ligase in ERAD, and when knocked down in cardiac myocytes, apoptosis occurs [142,143]. In A. thaliana, two homologs of HRD1, HRD1A/B, ubiquitinate misfolded proteins as part of ERAD [142]. An important partner of HRD1 is the integral membrane protein SEL1L in metazoa and its homolog HRD3 in plants, which contain a large ER luminal domain thought to be involved in the selection of terminally misfolded proteins for ERAD [144]. Although these genes are conserved from humans to plants, determination of complete functional conservation requires additional investigation [142]. Comprehensive reviews of ERAD can be found elsewhere [139–141], and here we focus primarily on showcasing dynamic control through PTMs and the plant-specific components (Figure 5B).

A. thaliana encodes 37 E2 ubiquitin-conjugating genes and some share homology with mammalian E2s. UBC32, an A. thaliana ERAD E2 [145], is kept at low levels in physiological conditions via ubiquitination and UPS-mediated degradation by HRD1 and other ubiquitin ligases involved in ERAD [146]. ER stress releases this negative regulation, increasing the capacity of ERAD [146]. UBC32 may be regulated by other PTMs similar to its mammalian homolog, UBE2J1, which is additionally modulated by phosphorylation to influence cell-fate outcomes in ER stress recovery [147]. A. thaliana E2s, UBC7, UBC13, and UBC14 share homology with the ERAD E2 genes UBC7 in yeast and UBC15 in metazoans with additive knockout mutations of UBC7, UBC13, and UBC14 showing sensitivity to ER stress, suggesting their involvement in ER stress survival [148]. The protein homology and strong phenotype of the ubc7/13/14 triple mutant in ER stress [148] suggest these are E2 ERAD components, or at least important for promoting homeostasis in ER stress.

Several plant-specific ERAD components related to ubiquitination dynamics have been identified. For example, EBS7, a plant-specific ERAD component that interacts with HRD1A and HRD3, is thought to regulate the cellular availability of HRD1A by preventing its autoubiquitination and UPS degradation [149]. Protein Associated With HRD1-1 (PAWH1) and PAWH2, also plant-specific components of ERAD that associate with HRD1A via EBS7, regulate the levels of EBS7 and HRD1A [150], potentially by suppressing HRD1A auto- and transubiquitination as an ER-tuning mechanism [141]. Without PAWH1/2, ERAD is compromised and there is decreased tolerance to ER stress [150]. Finally, EMR, a plant-specific cytosolic E3 ubiquitin-protein ligase associated with ERAD via an interaction with UBC32, promotes ERAD-mediated degradation of misfolded proteins [151]. Although an EMR knockout would be expected to impair ERAD and increase pro-death ER stress responses, an increase in ER stress tolerance was observed in an emr knockout [151]. This phenotype is likely due to partially misfolded brassinosteriod (BR) PM receptor, BRI1, evading ERAD to traffic to the PM where it promotes growth via BR signaling [151]. This distinction from other ERAD mutants suggests that various ERAD components may have different roles in ERAD pro-survival function during ER stress. Other ERAD components have been implicated in the escape of mutant BRI1, including UBC32 [145], HRD1A/HRD1B [152], and EBS7 [149].

DUBs like A. thaliana OTU1 [147] and mammalian USP19 and USP13 are critical for ERAD function. USP19 deubiquitinates HRD1, rescuing it from UPS-mediated degradation [153], while USP13 works in concert with the ERAD E3 ligase GP78 to maintain precise ubiquitination of the cytosolic ERAD component UBL4A [154]. Imbalance in UBL4A ubiquitination is detrimental to ER stress responses, supporting that fine-tuned ubiquitination is necessary for ERAD [154]. Therefore, despite a slower elucidation of ERAD components in plants, available results point to both conservation and divergence of the role of auto- and transubiquitination of ERAD components and targets in ER stress responses [155,156]. Further elucidation of ERAD components and PTM dynamics may reveal more insights into the regulation and potentially novel facets of ERAD that go beyond the degradation of misfolded proteins.

Role of UBL modification in ER-phagy

As a pro-life mechanism for alleviating ER stress, ER-phagy is dependent on UFMylation in response to stalled ribosomes [122] and salt stress-triggered ER stress [157]. In plants and metazoa, upon ribosomal stalling, the C53-UFL1-DDRGK1 complex transfers UFM1 to the ribosomal protein RPL26 [158,159] exposing a shuffled ATG8-interacting motif on C53 that recruits the autophagosome by binding to ATG8 for ER-phagy [122]. Also, in A. thaliana, in salt stress-triggered ER stress, UFL1, the UFM1 E3 ligase, directly interacts with ATG8 to recruit the autophagosome as well [157], underlining the importance of UFMylation and its machinery in prolonged ER stress-driven ER-phagy in plants (Figure 5C). Phosphorylation and arginylation are also involved in ER phagy in human cells [160], supporting the need for increased investigation into PTMs to better understand plant ER-phagy mechanisms.

Combining PTMs on master regulators of the UPR

Unsurprisingly, numerous PTMs can occur on the same protein, and IRE1 is an excellent example of this as it is subject to PTMs beyond phosphorylation. Outside a role in ER-phagy [122], DDRGK1 also controls mammalian IRE1a stability. UFM1 and UFL1-DDRGK1 prevent ER stress-induced apoptosis in pancreatic β cells and cells with heavy secretory loads [161], but there are conflicting reports of whether DDRGK1 promotes [162] or suppresses [163] IRE1a stability. Nonetheless, it is clear DDRGK1 and UFMylation influence cell-fate outcomes in ER stress by modulating major branches of the UPR [162–165]. Additionally, because DDRGK1 is conserved, understanding its influence on IRE1 abundance may provide insights into the regulation of the major plant UPR branch. In mammalian cells, additional ubiquitin and UBL modifications of IRE1 take place, including ubiquitination by the E3 ligase MITOL, which inhibits apoptosis [166], ubiquitination by E3 ligase CHIP, poised to increase IRE1a phosphorylation and drive apoptosis [167], and binding of the DUB USP14, which reduces IRE1 activation and downstream caspase-3 activation [168]. Because IRE1 is the most ancestral and conserved branch of the UPR, the extensive PTMs that regulate mammalian IRE1 activity levels suggest that evaluations of IRE1 PTMs in plants will yield similar complexity of regulation.

The bZIP28/ATF6 branch also exhibits ubiquitination and UBL modifications that influence ER stress outcomes. ER stress response elements (ERSEs) are cis-acting DNA sequences in the promoter regions of genes targeted by UPR TFs [75], and the TF HY5 binds ERSEs preventing bZIP28 from binding and driving expression of downstream UPR genes [169]. COP1, an E3 ubiquitin ligase, relocates to the nucleus in ER stress, ubiquitinates HY5 and triggers its degradation, allowing bZIP28 to bind the ERSEs [169,170] (Figure 4). Additionally, in mammalian cells experiencing chronic ER stress, ATF6 exhibits a reduction in its pro-life transcriptional activity due to SUMOylation in the nucleus likely operated by the E3 ligase PIAS1 [171]. ATF6 nuclear localization can be further manipulated by a complex web of PTMs, including SUMOylation and phosphorylation of itself and associated regulatory proteins [172]. In A. thaliana, these specific SUMOylation sites are not strongly conserved in bZIP28, however, a most up to date SUMOylation prediction tool, GPS-SUMO [173–175], predicts a strong SUMOylation site at K307 that is expected to be part of the proteolytically freed TF [72,176], suggesting that bZIP28 functionality may also be manipulated by SUMOylation.

Eukaryotic growth, development, and stress responses rely on regulated ER proteostasis. Accumulation of misfolded proteins in the ER can result in ER stress that is implicated in crop losses and myriad human diseases. Eukaryotic cells can sense and respond to ER stress by promoting the execution of homeostatic pathways or triggering pro-death pathways if the stress proves implacable. To date, the milieu of these decisions within the cell is unclear, but this review highlights the established role of PTMs and areas for their potential involvement. Major branches of the UPR exhibit complex PTM regulation directing cell-fate outcomes in ER stress and despite many PTMs having been identified in non-plant species, their parallel identification and extended characterization in plants during ER stress will be critical. Unbiased proteomics of the major branches of the UPR, TFs, and molecular chaperones will begin to clarify how PTM regulation directly impacts cell-fate decisions in ER stress and while studies suggest critical roles of PTMs in these decisions, following up on these leads is crucial to understanding the fine-tuned and temporally dynamic responses driving life or death.

  • Proteostasis disequilibrium of the ER forces cells to trigger life or death pathways to overcome proteotoxic stress, which has been linked to dramatic crop losses and devastating human diseases. Understanding the dynamics and mechanisms of these cellular decisions is critical for engineering resilient crops in the face of climate change and improving the lives of millions with ER stress-related diseases.

  • It is well established that ER stress can prompt both pro-life and pro-death responses, but the mechanisms and circumstances that drive one versus the other are not well understood in plants, especially at the level of protein PTMs. Genomics, proteomics, and other large-scale investigations of the mechanisms surrounding cellular decisions in ER stress are pointing to the fact that in addition to a stringent regulation of gene expression, PTMs play a significant role in ER stress outcomes.

  • Although genomics and genetics work has provided the much-needed context for probing the involvement of proteins in life-or-death decisions in ER stress, technological advancements in protein sequencing will allow the generation of novel and robust hypotheses and facilitate new questions regarding the role of proteoforms that arise from different protein variants and their PTMs in ER stress resolution.

The authors declare that there are no competing interests associated with the manuscript.

The authors’ work is supported by the National Institutes of Health [R35GM136637] and the National Science Foundation Graduate Research Fellowship Program under Grant No. 2235783 with contributing support from by the Great Lakes Bioenergy Research Center, U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research [DE-SC0018409], Chemical Sciences, Geoscience and Biosciences Division, Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy [DE-FG02-91ER20021] and MSU AgBioResearch (MICL02598).

ABI5

ABA insensitive 5

ATF6

activating transcription factor 6

BR

brassinosteriod

DUB

de-ubiquitinating enzyme

eIF2a

eukaryotic initiation factor 2 alpha

ER

endoplasmic reticulum

ERAD

ER-associated degradation

HSP

heat shock protein

IRE1

inositol requiring enzyme 1

PDI

protein disulfide isomerase

PERK

PKR-like ER kinase

PM

plasma membrane

PTM

post-translational modification

RIP

regulated intramembrane proteolysis

SBD

substrate binding domain

UBL

ubiquitin-like

UFM1

ubiquitin fold modifier-1

UPR

unfolded protein response

UPS

ubiquitin-proteasome system

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