bims-unfpre 2021-12-12 papers

Issue of 2021–12–12
six papers selected by
Susan Logue, University of Manitoba

Trends Pharmacol Sci. 2021 Dec 07. pii: S0165-6147(21)00228-5. [Epub ahead of print]

ER stress in obesity pathogenesis and management.

Amir Ajoolabady, Simin Liu, Daniel J Klionsky, Gregory Y H Lip, Jaakko Tuomilehto, Sina Kavalakatt, David M Pereira, Afshin Samali, Jun Ren.

Given the unprecedented global pandemic of obesity, a better understanding of the etiology of adiposity will be necessary to ensure effective management of obesity and related complications. Among the various potential factors contributing to obesity, endoplasmic reticulum (ER) stress refers to a state of excessive protein unfolding or misfolding that is commonly found in metabolic diseases including diabetes mellitus, insulin resistance (IR), and non-alcoholic fatty liver disease, although its role in obesogenesis remains controversial. ER stress is thought to drive adiposity by dampening energy expenditure, making ER stress a likely therapeutic target for the management of obesity. We summarize the role of ER stress and the ER stress response in the onset and development of obesity, and discuss the underlying mechanisms involved with a view to identifying novel therapeutic strategies for obesity prevention and management.

Keywords: ER stress; adaptive UPR; maladaptive UPR; obesity; unfolded protein response

DOI: https://doi.org/10.1016/j.tips.2021.11.011

Circ Res. 2021 Dec 06.

Unspliced XBP1 Counteracts β-catenin to Inhibit Vascular Calcification.

Liu Yang, Rongbo Dai, Hao Wu, Zeyu Cai, Nan Xie, Xu Zhang, Yicong Shen, Ze Gong, Yiting Jia, Fang Yu, Ying Zhao, Pinglan Lin, Chaoyang Ye, Yanhua Hu, Yi Fu, Qingbo Xu, Zhiqing Li, Wei Kong.

Background: Vascular calcification is a prevalent complication in chronic kidney disease and contributes to increased cardiovascular morbidity and mortality. XBP1 (X-box binding protein 1), existing as the unspliced (XBP1u) and spliced (XBP1s) forms, is a key component of the endoplasmic reticulum stress involved in vascular diseases. However, whether XBP1u participates in the development of vascular calcification remains unclear. Methods: We aim to investigate the role of XBP1u in vascular calcification.XBP1u protein levels were reduced in high phosphate (Pi)-induced calcified vascular smooth muscle cells (VSMCs), calcified aortas from mice with adenine diet-induced chronic renal failure (CRF) and calcified radial arteries from CRF patients. Results: Inhibition of XBP1u rather than XBP1s upregulated in the expression of the osteogenic markers runt-related transcription factor 2 (Runx2) and msh homeobox2 (Msx2), and exacerbated high Pi-induced VSMC calcification, as verified by calcium deposition and Alizarin red S staining. In contrast, XBP1u overexpression in high Pi-induced VSMCs significantly inhibited osteogenic differentiation and calcification. Consistently, SMC-specific XBP1 deficiency in mice markedly aggravated the adenine diet- and 5/6 nephrectomy-induced vascular calcification compared with that in the control littermates. Further interactome analysis revealed that XBP1u bound directly to β-catenin, a key regulator of vascular calcification, via aa 205-230 in its C-terminal degradation domain. XBP1u interacted with β-catenin to promote its ubiquitin-proteasomal degradation and thus inhibited β-catenin/T-cell factor (TCF)-mediated Runx2 and Msx2 transcription. Knockdown of β-catenin abolished the effect of XBP1u deficiency on VSMC calcification, suggesting a β-catenin-mediated mechanism. Moreover, the degradation of β-catenin promoted by XBP1u was independent of glycogen synthase kinase 3β (GSK-3β)-involved destruction complex. Conclusions: Our study identified XBP1u as a novel endogenous inhibitor of vascular calcification by counteracting β-catenin and promoting its ubiquitin-proteasomal degradation, which represents a new regulatory pathway of β-catenin and a promising target for vascular calcification treatment.

DOI: https://doi.org/10.1161/CIRCRESAHA.121.319745

Front Physiol. 2021 ;12 735580

Mechanisms of Hypercapnia-Induced Endoplasmic Reticulum Dysfunction.

Vitalii Kryvenko, István Vadász.

Protein transcription, translation, and folding occur continuously in every living cell and are essential for physiological functions. About one-third of all proteins of the cellular proteome interacts with the endoplasmic reticulum (ER). The ER is a large, dynamic cellular organelle that orchestrates synthesis, folding, and structural maturation of proteins, regulation of lipid metabolism and additionally functions as a calcium store. Recent evidence suggests that both acute and chronic hypercapnia (elevated levels of CO2) impair ER function by different mechanisms, leading to adaptive and maladaptive regulation of protein folding and maturation. In order to cope with ER stress, cells activate unfolded protein response (UPR) pathways. Initially, during the adaptive phase of ER stress, the UPR mainly functions to restore ER protein-folding homeostasis by decreasing protein synthesis and translation and by activation of ER-associated degradation (ERAD) and autophagy. However, if the initial UPR attempts for alleviating ER stress fail, a maladaptive response is triggered. In this review, we discuss the distinct mechanisms by which elevated CO2 levels affect these molecular pathways in the setting of acute and chronic pulmonary diseases associated with hypercapnia.

Keywords: carbon dioxide; endoplasmic reticulum; hypercapnia; protein folding; unfolded protein response

DOI: https://doi.org/10.3389/fphys.2021.735580

Front Aging Neurosci. 2021 ;13 767493

The Interplay of the Unfolded Protein Response in Neurodegenerative Diseases: A Therapeutic Role of Curcumin.

Sitabja Mukherjee, Awdhesh Kumar Mishra, G D Ghouse Peer, Sali Abubaker Bagabir, Shafiul Haque, Ramendra Pati Pandey, V Samuel Raj, Neeraj Jain, Atul Pandey, Santosh Kumar Kar.

Abnormal accumulation of misfolded proteins in the endoplasmic reticulum and their aggregation causes inflammation and endoplasmic reticulum stress. This promotes accumulation of toxic proteins in the body tissues especially brain leading to manifestation of neurodegenerative diseases. The studies suggest that deregulation of proteostasis, particularly aberrant unfolded protein response (UPR) signaling, may be a common morbific process in the development of neurodegeneration. Curcumin, the mixture of low molecular weight polyphenolic compounds from turmeric, Curcuma longa has shown promising response to prevents many diseases including current global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurodegenerative disorders. The UPR which correlates positively with neurodegenerative disorders were found affected by curcumin. In this review, we examine the evidence from many model systems illustrating how curcumin interacts with UPR and slows down the development of various neurodegenerative disorders (ND), e.g., Alzheimer's and Parkinson's diseases. The recent global increase in ND patients indicates that researchers and practitioners will need to develop a new pharmacological drug or treatment to manage and cure these neurodegenerative diseases.

Keywords: Alzheimer’s disease; ER stress; Parkinson’s disease; ROS—reactive oxygen species; cell death; curcumin; neurodegenaration; unfolded protein response

DOI: https://doi.org/10.3389/fnagi.2021.767493

Front Plant Sci. 2021 ;12 755447

The Endoplasmic Reticulum Role in the Plant Response to Abiotic Stress.

Sofía Reyes-Impellizzeri, Adrian A Moreno.

The endoplasmic reticulum (ER) is the organelle where one third of the proteins of a cell are synthetized. Several of these proteins participate in the signaling and response of cells, tissues, or from the organism to the environment. To secure the proper synthesis and folding of these proteins, or the disposal of unfolded or misfolded proteins, the ER has different mechanisms that interact and regulate each other. These mechanisms are known as the ER quality control (ERQC), ER-associated degradation (ERAD) and the unfolded protein response (UPR), all three participants of the maintenance of ER protein homeostasis or proteostasis. Given the importance of the client proteins of these ER mechanisms in the plant response to the environment, it is expected that changes or alterations on their components have an impact on the plant response to environmental cues or stresses. In this mini review, we focus on the impact of the alteration of components of ERQC, ERAD and UPR in the plant response to abiotic stresses such as drought, heat, osmotic, salt and irradiation. Also, we summarize findings from recent publications looking for a connection between these processes and their possible client(s) proteins. From this, we observed that a clear connection has been established between the ERAD and UPR mechanisms, but evidence that connects ERQC components to these both processes or their possible client(s) proteins is still lacking. As a proposal, we suggest the use of proteomics approaches to uncover the identity of these proteins and their connection with ER proteostasis.

Keywords: abiotic stress; chaperone; endoplasmic reticulum associated degradation (ERAD); endoplasmic reticulum quality control (ERQC); unfolded protein response (UPR)

DOI: https://doi.org/10.3389/fpls.2021.755447

J Chem Theory Comput. 2021 Dec 09.

Probing Interplays between Human XBP1u Translational Arrest Peptide and 80S Ribosome.

Francesco Di Palma, Sergio Decherchi, Fátima Pardo-Avila, Sauro Succi, Michael Levitt, Gunnar von Heijne, Andrea Cavalli.

The ribosome stalling mechanism is a crucial biological process, yet its atomistic underpinning is still elusive. In this framework, the human XBP1u translational arrest peptide (AP) plays a central role in regulating the unfolded protein response (UPR) in eukaryotic cells. Here, we report multimicrosecond all-atom molecular dynamics simulations designed to probe the interactions between the XBP1u AP and the mammalian ribosome exit tunnel, both for the wild type AP and for four mutant variants of different arrest potencies. Enhanced sampling simulations allow investigating the AP release process of the different variants, shedding light on this complex mechanism. The present outcomes are in qualitative/quantitative agreement with available experimental data. In conclusion, we provide an unprecedented atomistic picture of this biological process and clear-cut insights into the key AP-ribosome interactions.

DOI: https://doi.org/10.1021/acs.jctc.1c00796