Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

被引：8

作者：

Pacheco, Yves ^{[1
]}

Valeyre, Dominique ^{[2
]}

El Jammal, Thomas ^{[1
,3
]}

Vallee, Maxime ^{[4
]}

Chevalier, Fabien ^{[1
]}

Lamartine, Jerome ^{[1
]}

Sigaudo-Roussel, Dominique ^{[1
]}

Verrier, Bernard ^{[1
]}

Israel-Biet, Dominique ^{[5
]}

Freymond, Nathalie ^{[6
]}

Cottin, Vincent ^{[7
]}

Calender, Alain ^{[1
,8
]}

机构：

[1] Claude Bernard Univ Lyon I, Lab Tissue Biol & Therapeut Engn, IBCP, CNRS UMR5305, F-69007 Lyon, France

[2] Univ Sorbonne Paris Nord, Hosp Paris St Joseph, UMR INSERM 1272, F-75014 Paris, France

[3] Lyon Univ Hosp, Dept Internal Med, F-69007 Lyon, France

[4] Hosp Civils Lyon, Dept Bioinformat, F-69007 Lyon, France

[5] Georges Pompidou European Hosp, AP HP, Dept Pulmonol, F-75014 Paris, France

[6] Lyon South Hosp, Hosp Civils Lyon, Dept Resp Med, F-69007 Lyon, France

[7] Claude Bernard Lyon 1, Hosp Civils Lyon, Natl Reference Ctr Rare Pulm Dis, Dept Resp Med,Louis Pradel Hosp, F-69007 Lyon, France

[8] Univ Claude Bernard Lyon 1, Hosp Civils Lyon, Dept Genet, F-69500 Bron, France

来源：

CELLS | 2021年 / 10卷 / 08期

关键词：

sarcoidosis; COVID-19; SARS-CoV2; genetics; autophagy; TANK Binding Kinase 1; mitophagy; MITOCHONDRIAL DYSFUNCTION; CELL-RECEPTOR; COVID-19; COMPLEX; PROTEIN; BRD4; INHIBITORS; IMMUNITY; BINDING;

D O I：

10.3390/cells10081995

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

引用

页数：29

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