Preventing oxidative stress: a new role for XBP1

High levels of reactive oxygen species (ROS) damage cells and are believed to be associated with various human pathologies, including aging, carcinogenesis and neurodegenerative disorders.1–3 To minimize the damage, hosts evolve non-enzymatic and enzymatic antioxidant defenses, the latter include catalase, superoxide dismutases (SODs) and glutathione peroxidases (GPxs). Catalase catalyzes hydrogen peroxide decomposition and has a central role in defense against oxidants generated through various metabolic pathways.4 Catalase activity is high in the liver but is also found in the kidney and erythrocytes.5 Catalase also plays a crucial role in hematopoietic renewal cells, and maintains bone marrow stem cells.6 We recently reported that its expression level in multiple myeloma cells is a pivotal factor determining sensitivity to parthenolide (PTL),7 which strongly induces ROS and is a candidate anticancer agent against myeloid leukemia cells.8 Catalase gene expression is mainly regulated by CCAAT/enhancer-binding protein-β (C/EBP-β),9 which is a member of the basic region/leucine zipper (bZIP) family of transcription factors, and/or by nuclear factor Y (NF-Y), which directly binds to the CCAAT boxes.10 In addition, SOD1 gene expression is known to be regulated by C/EBP-β, and human phospholipid hydroperoxide GPx is regulated by both C/EBP-e and NF-Y.11,12 Thus, the CCAAT-binding proteins13 appear to be crucial for the regulation of their basal transcription. The transcriptional factor X-box-binding protein 1 (XBP1) belongs to the bZIP family and is activated by accumulating unfolded proteins and other endoplasmic reticulum (ER) stress factors.14,15 Upon ER stress, XBP1 mRNA is spliced and creates a translational frame shift.16 The spliced XBP1 regulates a subset of ER-resident chaperone genes in the unfold protein response and protects cells from ER stress.17,18 XBP1 is widely expressed in adult tissues, and essential for hepatogenesis, cardiac myogenesis and plasma cell differentiation.19–21 A recent gene profiling study identified many genes as direct targets of XBP1 and their expression is regulated in a distinct cell type- or condition-dependent manner.22 Importantly, the targets include a set of genes linked to DNA damage and repair pathways as well as redox homeostasis and oxidative stress responses. In addition, XBP1 is essential for survival during hypoxia.23 These accumulating data suggest that XBP1 governs a variety of biological activities. There are conflicting results regarding XBP1 functions in several types of stress. XBP1 overexpression confers resistance to growth factor deprivation and enhances proliferation independently of growth factors,24,25 whereas XBP1 knockdown induces resistance to several ER stresses.26,27 Thus, the precise functions of XBP1 remain obscure. As described above, some target genes of XBP1 are classified in categories unrelated to processes associated with ER function. One of the unexpected categories includes genes involved in redox homeostasis and oxidative stress responses,22 which strongly suggests that XBP1 protects cells from oxidative stress, but to our knowledge there are few studies of this possibility. In this study, we investigated a possible role of XBP1 in sensitivity to oxidative stress. We found that disruption of XBP1 enhanced sensitivity to oxidative stress, that is, it augmented ROS generation and persistent p38 phosphorylation. Interestingly, we found that XBP1 deletion or knockdown decreased expression of several antioxidant genes, including catalase, SOD1 and TRX1. Our results suggest a novel protective function for XBP1 against oxidative stress, probably, at least in part, through positive regulation of catalase expression.