Conserved and plant-unique strategies for overcoming endoplasmic reticulum stress

Abstract

Stress caused by environmental conditions or physiological growth can lead to an accumulation of unfolded proteins in the endoplasmic reticulum (ER) causing ER stress, which in turn triggers a cytoprotective mechanism termed the unfolded protein response (UPR). Under mild-short stress conditions the UPR can restore ER functioning and cell growth, such as reducing the load of unfolded proteins through the upregulation of genes involved in protein folding and in degrading mis-folded proteins, and through autophagy activation, but it can also lead to cell death under prolonged and severe stress conditions. A diversified suite of sensors has been evolved in the eukaryotic lineages to orchestrate the UPR most likely to suit the cell's necessity to respond to the different kinds of stress in a conserved as well as species-specific manner. In plants three UPR sensors cooperate with non-identical signaling pathways: the protein kinase inositol-requiring enzyme (IRE1), the ER-membrane-associated transcription factor bZIP28, and the GTP-binding protein β1 (AGB1). In this mini-review, we show how plants differ from the better characterized metazoans and fungi, providing an overview of the signaling pathways of the UPR, and highlighting the overlapping and the peculiar roles of the different UPR branches in light of evolutionary divergences in eukaryotic kingdoms.

Keywords: ER stress; UPR temporal activation; adaptation; apoptosis; autophagy; eukaryotes; programed cell death; unfolded protein response.

FIGURE 1

ER stress-sensing proteins in eukaryotes. (A) Schematic diagram of IRE1-like, PERK and ATF6-like proteins (not to scale). GTSs, Golgi trafficking signals; TM, transmembrane domain; S1P, site 1 protease cleavage site; S2P, site 2 protease cleavage site; bZIP, basic leucine zipper domain. (B) Phylogenetic tree analysis of IRE1-like proteins from Animalia (Homo sapiens, Mus musculus and Caenorhabditis elegans), Fungi (Saccharomyces cerevisiae) and Plantae (Arabidopsis thaliana) was constructed by the Unweighted Pair Group Method with Arithmetic Mean (UPGMA) method using MEGA6 software. NCBI reference sequences: IRE1 alpha (H.s)-NP_001424, IRE1 beta (H.s)-NP_150296, IRE1 alpha (M.m)-NP_076402, IRE1 beta (M.m)-NP_036146, IRE1a (C.e)-NP_001254135, IRE1b (C.e)-NP_001254136, IRE1 (S.c)-NP_011946, IRE1a (A.t)-NP_565419, IRE1b (A.t)-NP_568444. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Poisson correction method. (C) Phylogenetic tree analysis of ATF6-like proteins from Animalia (H. sapiens, M. musculus and C. elegans) and Plantae (A. thaliana) was constructed by the UPGMA method using MEGA6 software. NCBI reference sequences: ATF6 alpha (H.s)-NP_031374, ATF6 beta (H.s)-NP_001129625, ATF6 alpha (M.m)-NP_001074773, ATF6 beta (M.m)-NP_059102, ATF6 (C.e)-NP_510094, bZIP28 (A.t)-NP_187691. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Poisson correction method.

FIGURE 2

PR pathways in eukaryotes. Accumulation of unfolded proteins inside the ER lumen triggers to UPR that, during the first layer of response, leads the cell to adaptation. IRE1 is the only identified ER stress sensor in yeast and it is widely conserved in metazoan and plants. Moreover, additional ER stress sensors so far identified are bZIP28 and AGB1 in plants, and ATF6 and PERK1 in metazoan. Activation of PERK leads to phosphorylation of two proteins: Nrf2 that activates the transcription of genes involved in redox homeostasis; and eIF2α that decreases the overload of newly synthetized proteins into the ER and increases the specific translation of the transcription factor ATF4. Subsequently, ATF4 induces the expression of genes involved in amino acid metabolism, anti-oxidative stress response, folding, quality control and autophagy. The activation of IRE1 leads (1) to the selective degradation of mRNAs (RIDD) encoding ER-translocating proteins, decreasing the protein loading into the ER, and (2) to the translation of the bZIP transcription factors Xbp1/bZIP60/Hac1 mRNA in metazoan, plants and yeast, respectively, that upregulate the UPR target genes mainly involved in folding, quality control and autophagy. ATF6 in metazoans and bZIP28 in Arabidopsis are translocated into the Golgi apparatus and cleaved by Site1 and Site2 proteases, releasing the ATF6/bZIP28 transcription factors domain, which then translocates to the nucleus where it increases the expression of genes involved in folding, quality control and autophagy. Upon excessive and prolonged ER stress, all the UPR pathways lead to cell death in yeast, metazoan, and plants. In plants, the cell death executioners are still largely unknown, while in metazoan they have been partially defined. In detail, IRE1 regulates the cell death through the mRNA decay of UPR target genes and of anti-apoptotic protein (anti-Casp2). In addition, IRE1 interacting with TRAF2 triggers the ASK1/JNK pathway promoting apoptosis. Moreover, PERK/eIF2α/ATF4, IRE1, and ATF6 induce the expression of the transcription factor CHOP, involved in the induction of apoptosis. Blue, eukaryotes; black, metazoan; green, plants; pink, yeast. Figure adapted from Chen and Brandizzi (2012).