bims-unfpre 2022-11-06 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–11–06
ten papers selected by
Susan Logue, University of Manitoba

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.
The functions of IRE1α in neurodegenerative diseases: Beyond ER stress.
Atg8 and Ire1 in combination regulate the autophagy-related endoplasmic reticulum stress response in Candida albicans.
Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke.
Endoplasmic Reticulum Stress and Metabolism in Hepatocellular Carcinoma.
SCF-SKP2 E3 ubiquitin ligase links mTORC1-ER stress-ISR with YAP activation in murine renal cystogenesis.
CD248 induces a maladaptive unfolded protein response in diabetic kidney disease.
Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.
V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells.

EMBO J. 2022 Oct 31. e111952

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Felipe Cabral-Miranda, Giovanni Tamburini, Gabriela Martinez, Alvaro O Ardiles, Danilo B Medinas, Yannis Gerakis, Mei-Li Diaz Hung, René Vidal, Matias Fuentealba, Tim Miedema, Claudia Duran-Aniotz, Javier Diaz, Cristobal Ibaceta-Gonzalez, Carleen M Sabusap, Francisca Bermedo-Garcia, Paula Mujica, Stuart Adamson, Kaitlyn Vitangcol, Hernan Huerta, Xu Zhang, Tomohiro Nakamura, Sergio Pablo Sardi, Stuart A Lipton, Brian K Kennedy, Juan Pablo Henriquez, J Cesar Cárdenas, Lars Plate, Adrian G Palacios, Claudio Hetz.

  Aging is a major risk factor for neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors associated with synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Keywords:  ER stress; UPR; XBP1s; aging brain; proteostasis

DOI:  https://doi.org/10.15252/embj.2022111952
Ageing Res Rev. 2022 Nov 01. pii: S1568-1637(22)00216-1. [Epub ahead of print] 101774

The functions of IRE1α in neurodegenerative diseases: Beyond ER stress.

Ling Chen, Mingxia Bi, Zhen Zhang, Xixun Du, Xi Chen, Qian Jiao, Hong Jiang.

  Inositol-requiring enzyme 1 α (IRE1α) is a type I transmembrane protein that resides in the endoplasmic reticulum (ER). IRE1α, which is the primary sensor of ER stress, has been proven to maintain intracellular protein homeostasis by activating X-box binding protein 1 (XBP1). Further studies have revealed novel physiological functions of the IRE1α, such as its roles in mRNA and protein degradation, inflammation, immunity, cell proliferation and cell death. Therefore, the function of IRE1α is not limited to its role in ER stress; IRE1α is also important for regulating other processes related to cellular physiology. Furthermore, IRE1α is a significant factor in the regulation of neurodegenerative diseases that are caused by the phosphorylation of Tau protein, the accumulation of α-synuclein (α-syn) and the toxic effects of mutant Htt (mHtt). Therefore, targeting IRE1α is a valuable approach for treating neurodegenerative diseases and regulating cell function. This review discusses the role of IRE1α in different cellular processes, and emphasizes the importance of IRE1α in neurodegenerative diseases.

Keywords:  ER stress; IRE1α; XBP1; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.arr.2022.101774
Res Microbiol. 2022 Oct 31. pii: S0923-2508(22)00077-8. [Epub ahead of print] 103996

Atg8 and Ire1 in combination regulate the autophagy-related endoplasmic reticulum stress response in Candida albicans.

Jiawen Du, He Zhao, Mengsen Zhu, Yixuan Dong, Liping Peng, Jianrong Li, Qiang Zhao, Qilin Yu, Mingchun Li.

  The unfolded protein response (UPR) is an important pathway to prevent endoplasmic reticulum (ER) stress in eukaryotic cells. In Saccharomyces cerevisiae, Ire1 is a key regulatory factor required for HAC1 gene splicing for further production of functional Hac1 and activation of UPR gene expression. Autophagy is another mechanism involved in the attenuation of ER stress by ER-phagy, and Atg8 is a core protein in autophagy. Both autophagy and UPR are critical for ER stress response, but whether they act individually or in combination in Candida albicans is unknown. In this study, we explored the interaction between Ire1 and the autophagy protein Atg8 for the ER stress response by constructing the atg8Δ/Δire1Δ/Δ double mutant in the pathogenic fungus C. albicans. Compared to the single mutants atg8Δ/Δ or ire1Δ/Δ, atg8Δ/Δire1Δ/Δ exhibited much higher sensitivity to various ER stress-inducing agents and more severe attenuation of UPR gene expression under ER stress. Further investigations showed that the double mutant had a defect in ER-phagy, which was associated with attenuated vacuolar fusion under ER stress. This study revealed that Ire1 and Atg8 in combination function in the activation of the UPR and ER-phagy to maintain ER homeostasis under ER stress in C. albicans.

Keywords:  Candida albicans; ER-phagy; Ire1; endoplasmic reticulum; unfolded protein response

DOI:  https://doi.org/10.1016/j.resmic.2022.103996
Front Cell Neurosci. 2022 ;16 1016391

Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke.

Xuan Li, Ran Li, Liping Lu, Ashis Dhar, Huaxin Sheng, Wei Yang.

  Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activated. We have previously demonstrated that the UPR pathway initiated by ATF6 is pro-survival in transient ischemic stroke. However, the effect of ATF6 activation on the outcome after permanent ischemic stroke remains unknown. Here, we addressed this knowledge gap. Method: sATF6-KI mice with functional short-form ATF6 (sATF6) predominantly expressed in forebrain neurons were subjected to two ischemic stroke models: photothrombotic stroke and permanent middle cerebral artery occlusion (pMCAO). Both short-term and long-term functional outcomes were evaluated. Changes in neuroinflammation and cerebrovascular density after pMCAO were also assessed. Results: Compared to littermate controls, sATF6-KI mice performed significantly better in open field, cylinder, and foot fault tests on day 1 or 3 after photothrombotic stroke. However, on days 7 and 14 after stroke, the performance of these functional tests was not significantly different between groups, which is likely related to mild brain damage associated with this stroke model. Thus, to evaluate the long-term effects of ATF6 activation in permanent stroke, we turned to our pMCAO model. We first found that on day 4 after pMCAO, functional outcome was better, and infarct volumes were smaller in sATF6-KI mice vs controls. Next, the 15-day stroke outcome study indicated that compared to control mice, sATF6-KI mice consistently exhibited improved performance in neurologic scoring, tight rope test, and tape removal test, after pMCAO. Moreover, sATF6-KI mice showed higher vascular density and lower activation of both astrocytes and microglia around stroke regions on day 16 after pMCAO. Conclusions: Here, we presented the first evidence that activation of the ATF6 UPR branch is protective in permanent ischemic stroke, which further supports the therapeutic potential of targeting the ATF6 pathway in stroke.

Keywords:  ER stress; MCAO; UPR; long-term; photothrombotic stroke; proteostasis; transgenic mice

DOI:  https://doi.org/10.3389/fncel.2022.1016391
Am J Pathol. 2022 Oct 26. pii: S0002-9440(22)00322-4. [Epub ahead of print]

Endoplasmic Reticulum Stress and Metabolism in Hepatocellular Carcinoma.

Clara Luna-Marco, Anna Ubink, Maria Kopsida, Femke Heindryckx.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 85-90% of all liver cancer cases. It is a hepatocyte-derived primary tumour, causing 550,000 deaths per year, ranking it as one of the most common cancers worldwide. The liver is a highly metabolic organ with multiple functions, including digestion, detoxification, breakdown of fats, production of bile and cholesterol, in addition to storage of vitamins, glycogen and minerals, and synthesizing plasma proteins and clotting factors. Due to these fundamental and diverse functions, the malignant transformation of hepatic cells can have a severe impact on the liver´s metabolism. Furthermore, tumorigenesis is often accompanied by an activation of the endoplasmic reticulum (ER) stress pathways, which are known to be highly intertwined with several metabolic pathways. As HCC is characterized by changes in the metabolome and by an aberrant activation of the ER-stress pathways, the aim of this review is to summarize the available knowledge that links ER-stress and metabolism in HCC, thereby focusing on potential therapeutic targets.

DOI: https://doi.org/10.1016/j.ajpath.2022.09.012
J Clin Invest. 2022 Nov 03. pii: e153943. [Epub ahead of print]

SCF-SKP2 E3 ubiquitin ligase links mTORC1-ER stress-ISR with YAP activation in murine renal cystogenesis.

Dibyendu K Panda, Xiuying Bai, Yan Zhang, Nicholas A Stylianesis, Antonis E Koromilas, Mark L Lipman, Andrew C Karaplis.

  The Hippo pathway nuclear effector Yes-associated protein 1 (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1) driven by ERK1/2 and PI3K/AKT cascades induced endoplasmic reticulum (ER) proteotoxic stress. To reduce it by reprogramming translation, the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF-S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α-phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress-ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan, impeded these processes. Restoring ER homeostasis, and/or interfering with the SKP2-YAP interaction represent novel potential therapeutic avenues for stemming the progression of renal cystogenesis.

Keywords:  Chronic kidney disease; Nephrology

DOI:  https://doi.org/10.1172/JCI153943
Kidney Int. 2022 Oct 26. pii: S0085-2538(22)00904-8. [Epub ahead of print]

CD248 induces a maladaptive unfolded protein response in diabetic kidney disease.

Shruthi Krishnan, Jayakumar Manoharan, Hongjie Wang, Dheerendra Gupta, Sameen Fatima, Yanfei Yu, Akash Mathew, Zhen Li, Shrey Kohli, Constantin Schwab, Antje Körner, Peter R Mertens, Peter Nawroth, Khurrum Shahzad, Michael Naumann, Berend Isermann, Ronald Biemann.

  Dysfunction of mesangial cells plays a major role in the pathogenesis of diabetic kidney disease (DKD), the leading cause of kidney failure. However, the underlying molecular mechanisms are incompletely understood. By unbiased gene expression analysis of glucose-exposed mesangial cells, we identified the transmembrane receptor CD248, as the most upregulated gene and maladaptive unfolded protein response (UPR) as one of the most stimulated pathways. Upregulation of CD248 was further confirmed in glucose-stressed mesangial cells in vitro, in kidney glomeruli isolated from diabetic mice (streptozotocin; STZ and db/db models, representing type 1 and type 2 diabetes mellitus, respectively) in vivo, and in glomerular kidney sections from patients with DKD. Time course analysis revealed that glomerular CD248 induction precedes the onset of albuminuria, mesangial matrix expansion and maladaptive UPR activation (hallmarked by transcription factor C/EBP homologous protein (CHOP) induction) but is paralleled by loss of the adaptive UPR regulator spliced X box binding protein (XBP1). Mechanistically, CD248 promoted maladaptive UPR signaling via inhibition of the inositol requiring enzyme 1α (IRE1α)-mediated transcription factor XBP1 splicing in vivo and in vitro. CD248 induced a multiprotein complex comprising heat shock protein 90, BH3 interacting domain death agonist (BID) and IRE1α, in which BID impedes IRE1α-mediated XBP1 splicing and induced CHOP mediated maladaptive UPR signaling. While CD248 knockout ameliorated DKD-associated glomerular dysfunction and reverses maladaptive unfolded protein response signaling, concomitant XBP1 deficiency abolished the protective effect in diabetic CD248 knockout mice, supporting a functional interaction of CD248 and XBP1 in vivo. Hence, CD248 is a novel mesangial cell receptor inducing maladaptive UPR signaling in DKD.

Keywords:  CD248; CHOP; Diabetic kidney disease; glomerular damage; mesangial cells; sXBP1

DOI:  https://doi.org/10.1016/j.kint.2022.09.024
Dev Cell. 2022 Oct 25. pii: S1534-5807(22)00720-1. [Epub ahead of print]

Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.

Yangli Liu, Jun Zhou, Ning Zhang, Xueying Wu, Qian Zhang, Wenfeng Zhang, Xinyu Li, Ye Tian.

  Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor (GPCR), SRZ-75, that couples with Gαq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPRmt) activation in the intestine via the release of neuropeptides in Caenorhabditis elegans. Constitutive activation of Gαq signaling in the ADL neurons is sufficient to induce the intestinal UPRmt, leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPRmt activation in response to various forms of neuronal mitochondrial dysfunction. Thus, GPCR and its Gαq downstream signaling in two sensory neurons coordinate the systemic UPRmt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling for organismal-wide mitochondrial stress regulation.

Keywords:  ADL chemosensory neurons; G-protein-coupled receptor; GPCR; Gαq signaling; SRZ-75; UPR(mt); cell-non-autonomous regulation; the mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.devcel.2022.10.001
J Cell Biol. 2023 Jan 02. pii: e202205045. [Epub ahead of print]222(1):

V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.

Terytty Yang Li, Arwen W Gao, Xiaoxu Li, Hao Li, Yasmine J Liu, Amelia Lalou, Nagammal Neelagandan, Felix Naef, Kristina Schoonjans, Johan Auwerx.

To adapt mitochondrial function to the ever-changing intra- and extracellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1 and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.

DOI: https://doi.org/10.1083/jcb.202205045
Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2204443119

IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells.

Jing Yang, Jinyang Zhen, Wenli Feng, Zhenqian Fan, Li Ding, Xiaoyun Yang, Yumeng Huang, Hua Shu, Jing Xie, Xin Li, Jingting Qiao, Yuxin Fan, Jinhong Sun, Na Li, Tengli Liu, Shusen Wang, Xiaona Zhang, Peter Arvan, Ming Liu.

  Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in β cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in β cells, named IER3IP1-βKO and IER3IP1-iβKO, respectively. We found that IER3IP1-βKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated β-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with β-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β-cell maturation and proliferation, along with increased condensation of β-cell nuclear chromatin. Inducible β-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after β-cell early development. Importantly, IER3IP1 was decreased in β cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with β-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in β cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.

Keywords:  ER stress; IER3IP1; diabetes; β cell proliferation; β cell survival

DOI:  https://doi.org/10.1073/pnas.2204443119