biomedicines Review Roles of XBP1s in Transcriptional Regulation of Target Genes Sung-Min Park , Tae-Il Kang and Jae-Seon So * Department of Medical Biotechnology, Dongguk University, Gyeongju 38066, Gyeongbuk, Korea; [email protected] (S.-M.P.); [email protected] (T.-I.K.) * Correspondence: [email protected] Abstract: The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease. Citation: Park, S.-M.; Kang, T.-I.; Keywords: XBP1s; IRE1; ATF6; ER stress; unfolded protein response; UPR; RIDD So, J.-S. Roles of XBP1s in Transcriptional Regulation of Target Genes. Biomedicines 2021, 9, 791. https://doi.org/10.3390/ 1. Introduction biomedicines9070791 The endoplasmic reticulum (ER) plays an essential role in the synthesis, folding, as- sembly, and modification of transmembrane or secretory proteins [1,2]. Moreover, this Academic Editor: Gautam Sethi intracellular organelle participates in calcium storage, lipid synthesis, and the detoxifica- tion of xenobiotics, drugs, and metabolic by-products [1–3]. Proteins are modified and Received: 8 June 2021 oligomerized in the ER lumen; correctly folded proteins can thus exit the ER and reach Accepted: 5 July 2021 their final destination [4]. However, the perturbation of ER homeostasis results in the Published: 8 July 2021 accumulation of misfolded or unfolded protein in the ER lumen, leading to ER stress [5,6]. ER stress is closely related to various environmental, physiological, and pathological dis- Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in turbances, such as ER calcium deficiency, hypoxia, oxidative stress, malnutrition, infectious published maps and institutional affil- pathogens, cancers, neurodegenerative disorders, and metabolic diseases [6–8]. iations. In response to ER stress, the protein quality control system of ER activates three distinct signaling pathways known as the unfolded protein response (UPR) to restore ER homeostasis (Figure1)[ 9]. ER stress is recognized by the following ER sensor proteins in mammalian cells: inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) [9]. Each of these transmembrane Copyright: © 2021 by the authors. proteins controls distinct branches of UPR that regulate unique transcriptional or transla- Licensee MDPI, Basel, Switzerland. This article is an open access article tional programs [10,11]. UPR alleviates ER stress primarily via three mechanisms [9–12]: (1) distributed under the terms and UPR increases the protein folding capacity of ER by inducing the transcription of various conditions of the Creative Commons genes encoding molecular chaperones and folding enzymes; (2) UPR attenuates protein Attribution (CC BY) license (https:// translation, thereby reducing the burden on ER by inhibiting the translocation of new creativecommons.org/licenses/by/ proteins into ER; and (3) misfolded proteins in ER are retrotransported to the cytosol, 4.0/). polyubiquitinated, and degraded by the 26S proteasome, a process called ER-associated Biomedicines 2021, 9, 791. https://doi.org/10.3390/biomedicines9070791 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 27 Biomedicines 2021, 9, 791 2 of 26 new proteins into ER; and (3) misfolded proteins in ER are retrotransported to the cytosol, proteinpolyubiquitinated, degradation and (ERAD) degraded [ 13by, 14the]. 26S However, proteasome, if ER a process stress iscalled not relievedER-associated or is too severe, UPRprotein induces degradation apoptosis (ERAD) to [13, remove14]. However, the damaged if ER stress cells is [not15 –relieved17]. or is too severe, UPR induces apoptosis to remove the damaged cells [15–17]. Figure 1. Signaling pathways of UPR. Signaling pathways of UPR are mediated by three ER-resident Figure 1. Signaling pathways of UPR. Signaling pathways of UPR are mediated by three ER-resident proteins: IRE1, PERK, and ATF6. In the absence of ER stress, BiP binds to the ER luminal domain of proteins:the sensor IRE1, proteins PERK, and inhibits and ATF6. their activation. In the absence However, of ER ER stress,stress induces BiP binds the dissociation to the ER luminalof BiP domain of thefrom sensor the sensors, proteins which and activates inhibits UPR their transducers. activation. (A However,) IRE1 pathway: ER stress IRE1 has induces serine/threonine the dissociation of BiP fromkinase the and sensors, RNase domains which activates in the cytoplasmic UPR transducers. region. Upon (A ER) IRE1 stress, pathway: IRE1 is activated IRE1 has via serine/threonine oli- gomerization and autophosphorylation, leading to increased RNase activity. Activated IRE1 recog- kinasenizes the and stem-loop RNase domainsstructure of in Xbp1 thecytoplasmic mRNA and induces region. unconvention Upon ER stress,al splicing IRE1 by is cleaving activated 26 via oligomer- izationintronic and nucleotides. autophosphorylation, The spliced Xbp1 mRNA leading is translated to increased by frameshi RNaseft into activity. an active Activated transcription IRE1 recognizes thefactor, stem-loop XBP1s. Then, structure XBP1s of upregulatesXbp1 mRNA the expressi and induceson of UPR unconventional target genes, including splicing ER by chaper- cleaving 26 intronic ones, ERAD components, and lipid biosynthetic enzymes. Furthermore, IRE1 recognizes various nucleotides.mRNAs besides The Xbp1 spliced mRNAXbp1 as substratesmRNA isunder translated ER stress by and frameshift induces the into degradation an active of transcription these factor, XBP1s.mRNAs, Then, a process XBP1s known upregulates as regulated the expressionIRE-dependent of UPRdecay target(RIDD). genes, RIDD includingis a mechanism ER chaperones, that ERAD components,resolves ER stress and by lipid degrading biosynthetic mRNAs enzymes. encoding ER-targeted Furthermore, proteins, IRE1 th recognizesereby reducing various protein mRNAs besides loads into ER. (B) PERK pathway: PERK has a serine/threonine kinase domain in its cytoplasmic Xbp1region.mRNA ER stress as substratesinduces PERK under activation ER stress via oligomerization and induces and the autophosphorylation degradation of these in the mRNAs, ki- a process knownnase domain. as regulated Activated IRE-dependent PERK then phosph decayorylates (RIDD). the serine RIDD 51 residue is a mechanism of eIF2α, resulting that resolves in alle- ER stress by degradingviation of ER mRNAs stress by encoding attenuating ER-targeted translation. proteins,By contrast, thereby phosphorylated reducing eIF2 proteinα selectively loads intopro- ER. (B) PERK motes the translation of ATF4, which activates the transcription of CHOP and GADD34. After ER pathway: PERK has a serine/threonine kinase domain in its cytoplasmic region. ER stress induces stress resolution, GADD34 interacts with PP1 to induce eIF2α dephosphorylation, restoring protein PERKtranslation. activation However, via oligomerizationif ER stress is notand resolved, autophosphorylation CHOP induces apoptosis. in the kinase (C) ATF6 domain. pathway: Activated PERK thenATF6 phosphorylates has an N-terminal the b-ZIP serine domain 51 residue in the cyto of eIF2plasmicα, resulting region. ER in stress alleviation induces ofATF6 ER stresstranslo- by attenuating translation.cation from ER By to contrast, the Golgi phosphorylated apparatus, where eIF2 ATF6α selectivelyis cleaved by promotes S1P and S2P. the This translation proteolytic of ATF4, which cleavage produces the N-terminal region of ATF6, referred to as ATF6(N). ATF6(N) functions as an activatesactive transcription the transcription factor and of upregulates CHOP and targ GADD34.et genes encoding After ER chaperones, stress resolution, ERAD compo- GADD34 interacts withnents, PP1 and to XBP1. induce IRE1, eIF2 inositol-requiringα dephosphorylation, enzyme 1; restoringPERK, protein protein kinase translation. R-like ER kinase; However, ATF6, if ER stress is notactivating resolved, transcription CHOP induces factor 6; apoptosis. RNase, endori (C)bonuclease; ATF6 pathway: XBP1, X-box ATF6 binding has an protein N-terminal 1; ERAD, b-ZIP domain in ER-associated protein degradation; eIF2α, eukaryotic translation initiation factor 2α;