Le déficit en alpha-1 antitrypsine : modèle d’altération de l’homéostasie protéique ou protéostasie

Vignaud, Hélène; Cullin, Christophe; Bouchecareilh, Marion

doi:10.1016/j.rmr.2015.05.013

Cited by 4 publications

(4 citation statements)

References 97 publications

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“…From here it will be transported by the bloodstream to the lung where its activity is critical for the inhibition of proteases that degrade elastin, a key component of the extracellular matrix responsible for the elastic properties of the lungs [4, 5]. Therefore, hepatic production of 1AT is necessary for maintaining the protease/anti-protease balance in the serum [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

Joly¹,

Vignaud²,

Martino³

et al. 2017

PLoS ONE

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BackgroundThe most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors.MethodsWe used an innovative approach combining yeast genetic screens with next generation exome sequencing to identify and functionally characterize the genes involved in 1ATD associated liver disease.ResultsUsing yeast genetic screens, we identified HRD1, an Endoplasmic Reticulum Associated Degradation (ERAD) associated protein, as an inducer of Z-mediated toxicity. Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated.ConclusionThis powerful experimental pipeline allowed us to identify and functionally validate two genes involved in Z-1AT-mediated severe liver toxicity. This pilot study moves forward our understanding on genetic modifiers involved in 1ATD and highlights the UPR pathway as a target for the treatment of liver diseases associated with 1ATD. Finally, these findings support a larger scale screening for HERPUD1 R50H and HFE H63D variants in the sub-group of 1ATD patients developing significant chronic hepatic injuries (hepatomegaly, chronic cholestasis, elevated liver enzymes) and at risk developing liver cirrhosis.

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Section: Introductionmentioning

confidence: 99%

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

Joly¹,

Vignaud²,

Martino³

et al. 2017

PLoS ONE

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“…This concentration can increase rapidly, up to 2-5 times, during acute phases of inflammation and infection following cytokine (interleukins 1 and 6) and tumor necrosis factor (TNFα) activation [16]. In addition to its major role into inflammation regulation, AAT has been also shown to be involved in angiogenesis and tumor growth processes [17].…”

Section: Alpha 1-antitrypsinmentioning

confidence: 99%

“…The ER protein endoplasmic reticulum-Golgi intermediate compartment (ERGIC-53) has been identified as the main AAT cargo receptor to shuttle AAT from the ER to the Golgi [31]. AAT acquires the last maturation in the Golgi, which modifies the protein, post-translationally, by restructuring glycans (thought to help stabilize the fold) to attain its tertiary structure [17]. AAT appears in globular form before being secreted into the bloodstream.…”

Section: The Folded Aat Vs the Unfolded Z-aat In The Secretory Pathwaymentioning

confidence: 99%

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Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

Karataş

Bouchecareilh

2020

IJMS

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Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ∆F508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies.

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Living with the enemy: from protein-misfolding pathologies we know, to those we want to know

Emwas

Alghrably

Dhahri

et al. 2021

Ageing Research Reviews

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Le déficit en alpha-1 antitrypsine : modèle d’altération de l’homéostasie protéique ou protéostasie

Cited by 4 publications

References 97 publications

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

Living with the enemy: from protein-misfolding pathologies we know, to those we want to know

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