This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg) Nanyang Technological University, Singapore. From the unfolded protein response to metabolic diseases – lipids under the spotlight Ho, Nurulain; Xu, Chengchao; Thibault, Guillaume 2018 Ho, N., Xu, C., & Thibault, G. (2018). From the unfolded protein response to metabolic diseases – lipids under the spotlight. Journal of Cell Science, 131, jcs199307‑. https://hdl.handle.net/10356/87971 https://doi.org/10.1242/jcs.199307 © 2018 The Company of Biologists Ltd. This paper was published in Journal of Cell Science and is made available as an electronic reprint (preprint) with permission of The Company of Biologists Ltd. The published version is available at: [http://dx.doi.org/10.1242/jcs.199307]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. Downloaded on 26 Sep 2021 22:24:14 SGT © 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs199307. doi:10.1242/jcs.199307 REVIEW From the unfolded protein response to metabolic diseases – lipids under the spotlight Nurulain Ho1, Chengchao Xu2 and Guillaume Thibault1,* ABSTRACT 2013; Nguyen et al., 2008). Obesity is now a global health pandemic The unfolded protein response (UPR) is classically viewed as a stress afflicting individuals of both developing and developed countries response pathway to maintain protein homeostasis at the (NCD Risk Factor Collaboration, 2016). Obesity and dyslipidemia endoplasmic reticulum (ER). However, it has recently emerged that are contributing risk factors for metabolic diseases, such as non- the UPR can be directly activated by lipid perturbation, independently alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). of misfolded proteins. Comprising primarily phospholipids, NAFLD is the most prevalent liver disease worldwide that is marked sphingolipids and sterols, individual membranes can contain by the abnormal accumulation of fat in the liver (Younossi et al., hundreds of distinct lipids. Even with such complexity, lipid 2016). The progression of NAFLD to severe non-alcoholic distribution in a cell is tightly regulated by mechanisms that remain steatohepatitis (NASH) results in chronic inflammation of incompletely understood. It is therefore unsurprising that lipid hepatocytes, cirrhosis of hepatic tissue and hepatocellular dysregulation can be a key factor in disease development. Recent carcinoma, culminating in terminal liver damage (Michelotti advances in analysis of lipids and their regulators have revealed et al., 2013). Recent studies suggest that elevated levels of serum remarkable mechanisms and connections to other cellular pathways free saturated fatty acids, a consequence of dyslipidemia, play a role including the UPR. In this Review, we summarize the current in the damage caused to hepatocytes during NAFLD (Li et al., understanding in UPR transducers functioning as lipid sensors and 2009). Similarly, T2D has been associated with increased levels of β the interplay between lipid metabolism and ER homeostasis in the triglycerides and free fatty acids, eventually leading to -cell context of metabolic diseases. We attempt to provide a framework dysfunction and insulin resistance (Eto et al., 2002; Kelpe et al., consisting of a few key principles to integrate the different lines of 2002; Briaud et al., 2002). Contrary to the well-established roles of evidence and explain this rather complicated mechanism. the UPR in resolving protein misfolding, the UPR as a contributor of lipotoxic cell death in the liver and pancreatic β-cells are poorly KEY WORDS: Endoplasmic reticulum stress, Unfolded protein characterized (Alkhouri et al., 2009; DeFronzo, 2004). This Review response, Lipid perturbation, Phospholipids, Metabolic diseases will briefly describe the classical functions of the UPR in maintaining ER protein homeostasis, before discussing the Introduction importance of lipid species in ER membrane homeostasis. The The key factors in the unfolded protein response (UPR) were different types of membrane irregularities affecting ER homeostasis identified during the search for factors required for endoplasmic mentioned here will be referred to collectively as ‘lipid bilayer reticulum (ER)-to-nucleus communication (Mori et al., 1992; stress’. We will discuss insights that have been derived from the Kohno et al., 1993; Mori et al., 1993; Cox et al., 1993; Cox and yeast Saccharomyces cerevisiae and substantiated with evidence Walter, 1996). The establishment of the UPR field was rather from mammalian in vitro and in vivo models. We will also examine serendipitous, but nevertheless it surprised the scientific community the intricacy between lipid bilayer stress and the UPR and by setting up a paradigm of unconventional signal transduction. emphasize the implications that are relevant for disease progression. Since then, the field has been ever expanding, just like any other fundamental discovery. As a means of coping with misfolded The unfolded protein response sensors proteins and restoring ER homeostasis, it is unsurprising that the As an ancient counter-stress programme to ease the damaging effects UPR is directly linked to protein-misfolding disorders, such as in the ER, extensive efforts have been made to better understand the Alzheimer’s disease and Parkinson’s disease (Hetz and Saxena, UPR. Typically, the accumulation of unfolded proteins in the ER 2017). Cancer cells exploit the UPR to sustain their high demand for activates the three ER-stress transducers, inositol-requiring enzyme protein production, which is a prerequisite for unconditional 1α (Ire1α; also known as ERN1 in mammals), PRKR-like proliferation (Urra et al., 2016). Current evidence also shows a endoplasmic reticulum kinase (PERK; also known as EIF2AK3) clear association between the UPR and the hallmarks of metabolic and activating transcription factor 6 (ATF6), resulting in translational syndrome, dyslipidemia and obesity (Basseri and Austin, 2012; control and transcriptional reprogramming of UPR target genes to Cnop et al., 2012). Dyslipidemia, characterized as an increase in elicit global cellular changes (Walter and Ron, 2011) (Fig. 1). fasting and postprandial serum triglyceride (TAG) and cholesterol Ire1α is the most evolutionarily conserved UPR sensor and it is also levels, is a common feature observed in obese patients (Klop et al., solely present in lower eukaryotes such as S. cerevisiae and Schizosaccharomyces pombe (referredtoasScIre1andSpIre1, respectively, for clarity). The luminal domain of Ire1α directly binds to 1School of Biological Sciences, Nanyang Technological University, Singapore, 637551. 2Whitehead Institute for Biomedical Research, 455 Main Street, misfolded proteins through a dimeric interface peptide binding groove Cambridge, MA 02142-1479, USA. (Zhou et al., 2006; Gardner and Walter, 2011; Carrara et al., 2015), which triggers formation of dimers and higher-ordered oligomers *Author for correspondence ([email protected]) leading to trans-autophosphorylation (Gardner and Walter, 2011). N.H., 0000-0001-5039-0682; G.T., 0000-0002-7926-4812 Phosphorylated Ire1α/ScIre1 possesses a ribonuclease activity that Journal of Cell Science 1 REVIEW Journal of Cell Science (2018) 131, jcs199307. doi:10.1242/jcs.199307 Fig. 1. Activation of the unfolded protein A Mammals response (UPR). (A) In mammals, the α Ire1 PERK ATF6 accumulation of unfolded proteins or lipid bilayer stress (LBS) in the ER activates three Unfolded LBS protein distinct UPR sensors. Upon sensing of ER stress, monomeric Ire1α and PERK1 form ER lumen dimers or higher oligomers, followed by trans-autophosphorylation. The Ire1α ribonuclease domain cleaves the intron of u P P XBP1 P P XBP1 mRNAs, and newly synthesized P P P P XBP1 activates the transcription of UPR s XBP1 Cleavage α in Golgi target genes. Ire1 may also initiate P regulated Ire1-dependent decay (RIDD) of a RIDD RIDD specific subset of mRNA to decrease mRNA κ eIF2α ATF6(N) load. JNK and NF- B are activated by Ire1 Xbp1 and initiate the transcription of Translation proinflammatory genes. Activated PERK Ire1α-induced ATF6-induced phosphorylates eIF2α, resulting in the gene gene expression GADD34 ATF4 expression temporary attenuation of general translation and the activation of the transcription factor Cytosol/nucleus PERK-induced ATF4, which subsequently activates the gene expression transcription of specific UPR target genes JNK NF-κB such as CHOP and GADD34 (shown in dark blue). CHOP is a pro-apoptotic factor that Apoptosis Inflammatory genes initiates cell death and is also linked to NF- CHOP κB activation. Subsequently, GADD34 promotes the dephosphorylation of eIF2α, B S. cerevisiae C S. pombe resuming translation. When sensing unfolded proteins, the ATF6 luminal domain Ire1 Ire1 stimulates its relocalisation to the Golgi where the transcription factor is released by intramembrane proteolysis. Soluble ATF6 then translocates to the nucleus (N) where it upregulates the expression of a subset of UPR target genes. (B) S. cerevisiae Ire1 (ScIre1) undergoes dimerization or u P P HAC1 P P P P P P higher oligomerization and trans- autophosphorylation resulting in the splicing s HAC1 of HAC1 mRNA by its RNase domain. RIDD Transcription factor