Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2 ^−/− and Ripk2 ^−/− mice are hypersusceptible to influenza A virus infection. Ripk2 ^−/− cells displayed defective mitophagy leading to enhanced mitochondrial superoxide production and accumulation of damaged mitochondria resulting in increased NLRP3 inflammasome activation and IL-18 production. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1 ^−/− cells displayed enhanced mitochondrial superoxide production and caspase-1 activation. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating NLRP3 inflammasome activation and IL-18 production via ULK1-dependent mitophagy.

Related collections

Most cited references 25

Record: found
Abstract: found
Article: not found

Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

Tatsuya Saitoh, Naonobu Fujita, Myoung Ho Jang … (2008)

Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.

0 comments Cited 702 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

1918 Influenza: the Mother of All Pandemics

Jeffery K Taubenberger, David M. Morens (2006)

The "Spanish" influenza pandemic of 1918–1919, which caused ≈50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.

0 comments Cited 467 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: not found
Article: not found

Essential role for Nix in autophagic maturation of erythroid cells.

Swapan K. Dasgupta, Josef T Prchal, Jin-Wang Wei … (2008)

Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation. Although autophagy has been suggested to mediate the elimination of organelles for erythroid maturation, the molecular mechanisms underlying this process remain undefined. Here we report a role for a Bcl-2 family member, Nix (also called Bnip3L), in the regulation of erythroid maturation through mitochondrial autophagy. Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. Erythrocytes in the peripheral blood of Nix(-/-) mice exhibited mitochondrial retention and reduced lifespan in vivo. Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. Deficiency in Nix inhibited the loss of mitochondrial membrane potential (DeltaPsi(m)), and treatment with uncoupling chemicals or a BH3 mimetic induced the loss of DeltaPsi(m) and restored the sequestration of mitochondria into autophagosomes in Nix(-/-) erythroid cells. These results suggest that Nix-dependent loss of DeltaPsi(m) is important for targeting the mitochondria into autophagosomes for clearance during erythroid maturation, and interference with this function impairs erythroid maturation and results in anaemia. Our study may also provide insights into molecular mechanisms underlying mitochondrial quality control involving mitochondrial autophagy.

0 comments Cited 382 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 20 February 2013

Publication date (Electronic): 24 March 2013

Publication date (Print): May 2013

Publication date PMC-release: 24 September 2013

Volume: 14

Issue: 5

Pages: 480-488

Affiliations

[1 ]Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States

[2 ]Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States

[3 ]Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, United States

[4 ]Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Harvard Medical School, Boston, Massachusetts 02114, United States

[5 ]Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States

[6 ]The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States

[7 ]Department of Biochemistry, Ghent University, VIB, B-9000 Ghent, Belgium

[8 ]Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium

[9 ]Department of Medicine, University of Colorado Denver, Aurora, CO 80045, United States

[10 ]Department of Microbiology and Immunology, University of Melbourne, Vic 3010, Australia

Author notes

Correspondence should be addressed to: Thirumala-Devi Kanneganti Department of Immunology, MS #351 St Jude Children's Research Hospital 262 Danny Thomas Place Memphis TN 38105-2794, USA Tel: (901) 595-3634; FAX: (901) 595-5766 Thirumala-Devi.Kanneganti@ 123456stjude.org

Article

Manuscript ID: NIHMS439413

DOI: 10.1038/ni.2563

PMC ID: 3631456

PubMed ID: 23525089

SO-VID: 7df25e3e-82ec-473f-9e63-3a232331fe27

License:

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

History

Funding

Funded by: National Cancer Institute : NCI

Award ID: R01 CA163507 || CA

Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS

Award ID: R01 AR056296 || AR

Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID

Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection

Read this article at

Abstract

Related collections

Gamma Delta T cells

Most cited references 25

Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

1918 Influenza: the Mother of All Pandemics

Essential role for Nix in autophagic maturation of erythroid cells.

Author and article information

Journal

Affiliations

Author notes

Article

History

Funding

Categories

Comments

Comment on this article

Similar content 648

Cited by 171

Most referenced authors 1,018