Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy

Vanhoutte, Davy; Schips, Tobias G.; Vo, Alexander; Grimes, Kelly M.; Baldwin, Tanya A.; Brody, Matthew J.; Accornero, Federica; Sargent, Michelle A.; Molkentin, Jeffery D

doi:10.1038/s41467-021-24215-4

Cited by 93 publications

(70 citation statements)

References 60 publications

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“…The data support the concept that manipulation of PDIA3 activity may provide a new opportunity to manipulate the composition of ECM and, thereby, the local physiological microenvironment and cell behaviors. While this paper was in review, an interaction between TSP1 and the ER stress response mediator protein kinase R-like ER kinase (PERK) was published ( 57 ). In this study, overexpression of TSP1 in vivo, in cardiomyocytes, activated the PERK ER stress pathway.…”

Section: Discussionmentioning

confidence: 99%

PDIA3/ERp57 promotes a matrix-rich secretome that stimulates fibroblast adhesion through CCN2

Hellewell

Heesom

Jepson

et al. 2022

American Journal of Physiology-Cell Physiology

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The matricellular glycoprotein thrombospondin1 (TSP1) has complex roles in the extracellular matrix and at cell surfaces, but relatively little is known about its intracellular associations prior to secretion. To search for novel intracellular interactions of TSP1 in situ, we carried out a biotin ligase-based TSP1 interactome screen and identified protein disulphide isomerase A3 (PDIA3/ERp57) as a novel candidate binding protein. In validation, TSP1 and PDIA3 were established to bind in vitro and to colocalise in the endoplasmic reticulum of human dermal fibroblasts (HDF). Loss of PDIA3 function, either by pharmacological inhibition in HDF or in Pdia3-/- mouse embryo fibroblasts (Pdia3-/- MEF), led to alterations in the composition of cell-derived ECM, involving changed abundance of fibronectin and TSP1, and was correlated with reduced cell spreading, altered organisation of F-actin and reduced focal adhesions. These cellular phenotypes of Pdia3-/- MEF were normalised by exposure to conditioned medium (WTCM) or extracellular matrix (WTECM) from wild-type (WT)-MEF. Rescue depended on PDIA3 activity in WT-MEF, and was not prevented by immunodepletion of fibronectin. Heparin-binding proteins in WTCM were found to be necessary for rescue. Comparative quantitative tandem-mass-tag proteomics and functional assays on the heparin-binding secretomes of WT-MEF and Pdia3-/- MEF identified multiple ECM and growth factor proteins to be down-regulated in the CM of Pdia3-/- MEF. Of these, CCN2 was identified to be necessary for the adhesion-promoting activity of WTCM on Pdia3-/- MEF and to bind TSP1. Thus, PDIA3 coordinates fibroblast production of an ECM-rich, pro-adhesive microenvironment, with implications for PDIA3 as a translational target.

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Section: Discussionmentioning

confidence: 99%

PDIA3/ERp57 promotes a matrix-rich secretome that stimulates fibroblast adhesion through CCN2

Hellewell

Heesom

Jepson

et al. 2022

American Journal of Physiology-Cell Physiology

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“…A recent article highlighted that all arms of the UPR were activated and associated with replicative senescence in WI38 cells, and in H2O2-induced senescence, the same cells, only the PERK branch was activated [71]. In addition, this signaling pathway has also been associated with myocardial ischemia, hypertension, cardiac atrophy, hypertrophy, or even vascular calcification [43][44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

“…These factors are capable of increasing the folding capacity of the endoplasmic reticulum [42]. An important difference between the signaling pathways is that the PERK-ATF4-CHOP pathway is related to myocardial ischemia, hypertension, cardiac atrophy, hypertrophy, or even vascular calcification [43][44][45][46][47], while the IRE1 and ATF6 pathways may have cardioprotective effects [43,48].…”

Section: Introductionmentioning

confidence: 99%

Bisphenol A Induces Accelerated Cell Aging in Murine Endothelium

Moreno-Gómez-Toledano

Sánchez-Esteban

Cook

et al. 2021

Biomolecules

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Bisphenol A (BPA) is a widespread endocrine disruptor affecting many organs and systems. Previous work in our laboratory demonstrated that BPA could induce death due to necroptosis in murine aortic endothelial cells (MAECs). This work aims to evaluate the possible involvement of BPA-induced senescence mechanisms in endothelial cells. The β-Gal assays showed interesting differences in cell senescence at relatively low doses (100 nM and 5 µM). Western blots confirmed that proteins involved in senescence mechanisms, p16 and p21, were overexpressed in the presence of BPA. In addition, the UPR (unfolding protein response) system, which is part of the senescent phenotype, was also explored by Western blot and qPCR, confirming the involvement of the PERK-ATF4-CHOP pathway (related to pathological processes). The endothelium of mice treated with BPA showed an evident increase in the expression of the proteins p16, p21, and CHOP, confirming the results observed in cells. Our results demonstrate that oxidative stress induced by BPA leads to UPR activation and senescence since pretreatment with N-acetylcysteine (NAC) in BPA-treated cells reduced the percentage of senescent cells prevented the overexpression of proteins related to BPA-induced senescence and reduced the activation of the UPR system. The results suggest that BPA participates actively in accelerated cell aging mechanisms, affecting the vascular endothelium and promoting cardiovascular diseases.

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“…Thus, targeting CD47 in acute renal injury could ameliorate of renal function following injury [237]. Finally, it is worth noting that the anti-angiogenic Thbs1 has been recently identified as an autophagy activator by triggering the PERK-eF2α-ATF4 stress axis [238], similar to that evoked by anti-angiogenic endorepellin in endothelial cells [239]. Specifically, Thbs1, but not Thbs2-4, induces lethal cardiac atrophy via stress-evoked autophagy and acts as a critical regulator of cardiomyocyte size in the stressed heart [238].…”

Section: The Field Is Expanding: Heparanase and Thrombospondinmentioning

confidence: 99%

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth

Chen

Iozzo

2022

Open Biol.

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The extracellular matrix (ECM) exists as a dynamic network of biophysical and biochemical factors that maintain tissue homeostasis. Given its sensitivity to changes in the intra- and extracellular space, the plasticity of the ECM can be pathological in driving disease through aberrant matrix remodelling. In particular, cancer uses the matrix for its proliferation, angiogenesis, cellular reprogramming and metastatic spread. An emerging field of matrix biology focuses on proteoglycans that regulate autophagy, an intracellular process that plays both critical and contextual roles in cancer. Here, we review the most prominent autophagic modulators from the matrix and the current understanding of the cellular pathways and signalling cascades that mechanistically drive their autophagic function. We then critically assess how their autophagic functions influence tumorigenesis, emphasizing the complexities and stage-dependent nature of this relationship in cancer. We highlight novel emerging data on immunoglobulin-containing and proline-rich receptor-1, heparanase and thrombospondin 1 in autophagy and cancer. Finally, we further discuss the pro- and anti-autophagic modulators originating from the ECM, as well as how these proteoglycans and other matrix constituents specifically influence cancer progression.

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Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy

Cited by 93 publications

References 60 publications

PDIA3/ERp57 promotes a matrix-rich secretome that stimulates fibroblast adhesion through CCN2

PDIA3/ERp57 promotes a matrix-rich secretome that stimulates fibroblast adhesion through CCN2

Bisphenol A Induces Accelerated Cell Aging in Murine Endothelium

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth

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