Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection

被引：101

作者：

Munnur, Deeksha ^{[1
]}

Teo, Qiwen ^{[2
]}

Eggermont, Denzel ^{[3
,4
]}

Lee, Horace H. Y. ^{[2
,5
]}

Thery, Fabien ^{[3
]}

Ho, Julian ^{[2
]}

van Leur, Sophie Wilhelmina ^{[1
]}

Ng, Wilson W. S. ^{[2
]}

Siu, Lewis Y. L. ^{[2
]}

Beling, Antje ^{[6
,7
,8
,9
]}

Ploegh, Hidde ^{[10
,11
]}

Pinto-Fernandez, Adan ^{[12
]}

Damianou, Andreas ^{[12
]}

Kessler, Benedikt ^{[12
]}

Impens, Francis ^{[3
,4
,13
]}

Mok, Chris Ka Pun ^{[2
,14
,15
]}

Sanyal, Sumana ^{[1
,2
]}

机构：

[1] Univ Oxford, Sir William Dunn Sch Pathol, South Parks Rd, Oxford, England

[2] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, HKU Pasteur Res Pole, Hong Kong, Peoples R China

[3] VIB UGent Ctr Med Biotechnol, Ghent, Belgium

[4] Univ Ghent, Dept Biomol Med, Ghent, Belgium

[5] Univ Hong Kong, Dept Pathol, Hong Kong, Peoples R China

[6] Charite Univ Med Berlin, Berlin, Germany

[7] Free Univ Berlin, Berlin, Germany

[8] Humboldt Univ, Inst Biochem, Berlin, Germany

[9] Teutsches Zentrum Herz Kreislauf Forsch, Partner Site Berlin, Berlin, Germany

[10] Boston Childrens Hosp, Boston, MA USA

[11] Harvard Med Sch, Boston, MA 02115 USA

[12] Univ Oxford, Target Discovery Inst, Nuffield Dept Med, Mass Spectrometry Lab, Oxford, England

[13] VIB Prote Core, Ghent, Belgium

[14] Chinese Univ Hong Kong, Fac Med, Li Ka Shing Inst Hlth Sci, Hong Kong, Peoples R China

[15] Chinese Univ Hong Kong, Fac Med, Jockey Club Sch Publ Hlth & Primary Care, Hong Kong, Peoples R China

来源：

NATURE IMMUNOLOGY | 2021年 / 22卷 / 11期

基金：

新加坡国家研究基金会; 英国医学研究理事会; 英国惠康基金;

关键词：

INFLUENZA-A VIRUS; I INTERFERON; VIRAL REPLICATION; EPITHELIAL-CELLS; ISG15; PROTEIN; EXPRESSION; INDUCTION; PATHOLOGY; SEVERITY;

D O I：

10.1038/s41590-021-01035-8

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The antiviral factor ISG15 can be conjugated to other proteins through ISGylation. Sanyal and colleagues find that viruses can modulate ISGylation, which in turn alters macrophage responses and can result in exaggerated inflammation in COVID-19. Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.

引用

页码：1416 / +

页数：18

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[1] Secretory lysosomes [J].