Dataset Information

Regulation of the ER stress response by a mitochondrial microprotein

ABSTRACT: Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER-mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an unprecedented role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jolene Diedrich

LAB HEAD: Alan Saghatelian

PROVIDER: PXD014890 | Pride | 2019-11-12

REPOSITORIES: Pride

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			Action	DRS
	20151128_FlagIP-Mock-01_1.raw	Raw
	20151128_FlagIP-Mock-01_1.sqt	Other
	20151128_FlagIP-Mock-01_2.raw	Raw
	20151128_FlagIP-Mock-01_2.sqt	Other
	20151128_FlagIP-Mock-02_1.raw	Raw

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Regulation of the ER stress response by a mitochondrial microprotein.

Chu Qian Q Martinez Thomas F TF Novak Sammy Weiser SW Donaldson Cynthia J CJ Tan Dan D Vaughan Joan M JM Chang Tina T Diedrich Jolene K JK Andrade Leo L Kim Andrew A Zhang Tong T Manor Uri U Saghatelian Alan A

Nature communications 20191025 1

Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial oute ...[more]

PMID: 31653868

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Project description:Erguler2013 - Unfolded protein stress response The model investigates the mechanism by which UPR (unfolded protein response) outcome switches between survival and death. This model is described in the article: A mathematical model of the unfolded protein stress response reveals the decision mechanism for recovery, adaptation and apoptosis. Erguler K, Pieri M, Deltas C. BMC Syst Biol. 2013 Feb 21;7(1):16. Abstract: BACKGROUND: The unfolded protein response (UPR) is a major signalling cascade acting in the quality control ofprotein folding in the endoplasmic reticulum (ER). The cascade is known to play an accessory rolein a range of genetic and environmental disorders including neurodegenerative and cardiovasculardiseases, diabetes and kidney diseases. The three major receptors of the ER stress involved withthe UPR, i.e. IRE1a, PERK and ATF6, signal through a complex web of pathways to convey anappropriate response. The emerging behaviour ranges from adaptive to maladaptive depending on theseverity of unfolded protein accumulation in the ER; however, the decision mechanism for the switchand its timing have so far been poorly understood. RESULTS: Here, we propose a mechanism by which the UPR outcome switches between survival and death.We compose a mathematical model integrating the three signalling branches, and perform a comprehensivebifurcation analysis to investigate possible responses to stimuli. The analysis reveals threedistinct states of behaviour, low, high and intermediate activity, associated with stress adaptation, tolerance,and the initiation of apoptosis. The decision to adapt or destruct can, therefore, be understoodas a dynamic process where the balance between the stress and the folding capacity of the ER playsa pivotal role in managing the delivery of the most appropriate response. The model demonstratesfor the first time that the UPR is capable of generating oscillations in translation attenuation and theapoptotic signals, and this is supplemented with a Bayesian sensitivity analysis identifying a set ofparameters controlling this behaviour. CONCLUSIONS: This work contributes largely to the understanding of one of the most ubiquitous signalling pathwaysinvolved in protein folding quality control in the metazoan ER. The insights gained have direct consequenceson the management of many UPR-related diseases, revealing, in addition, an extended listof candidate disease modifiers. Demonstration of stress adaptation sheds light to how preconditioningmight be beneficial in manifesting the UPR outcome to prevent untimely apoptosis, and paves the wayto novel approaches for the treatment of many UPR-related conditions. In the paper, PERKA refers to the amount of phosphorylated PERK monomer. However, it refers to the active complex in the model. The complex with the model parameterization is formed of 4 monomers (n=4). So, the value of PERKA should be multiplied by 4, in order to generate the figures in the paper (eg. Figure 12). An additional parameter (tmr=10)) is used in the model. This parameter is not mentioned in the paper. The model values of kf(=10) and kr(=1) are not consistent with that of the paper (kf=100, kr=10, in the paper). However, this is corrected by the introduction of "tmr" in the model, which is multiplied with kf and kr to get the resulting values. The term "tmr" was missing in the kinetic laws of the reactions reu7 and reu8, in the original model. This has been corrected as per the author's request. This model is hosted on BioModels Database and identified by: MODEL1302180000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response This model is described in the article: A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response. Diedrichs DR, Gomez JA, Huang CS, Rutkowski DT, Curtu R. Mol. Biol. Cell 2018 Apr; : mbcE17090565 Abstract: The vertebrate unfolded protein response (UPR) is characterized by multiple interacting nodes among its three pathways, yet the logic underlying this regulatory complexity is unclear. To begin to address this issue, we created a computational model of the vertebrate UPR that was entrained upon and then validated against experimental data. As part of this validation, the model successfully predicted the phenotypes of cells with lesions in UPR signaling, including a surprising and previously unreported differential role for the eIF2? phosphatase GADD34 in exacerbating severe stress but ameliorating mild stress. We then used the model to test the functional importance of a feed-forward circuit within the PERK/CHOP axis, and of cross-regulatory control of BiP and CHOP expression. We found that the wiring structure of the UPR appears to balance the ability of the response to remain sensitive to ER stress yet also to be rapidly deactivated by improved protein folding conditions. This model should serve as a valuable resource for further exploring the regulatory logic of the UPR. This model is hosted on BioModels Database and identified by: MODEL1803300000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.