Autophagy in immunity and inflammation

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Abstract

Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy — the 'autophagy proteins' — orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

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Most cited references 56

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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.

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Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

Elizabeth L. Axe, Simon A. Walker, Maria Manifava … (2008)

Autophagy is the engulfment of cytosol and organelles by double-membrane vesicles termed autophagosomes. Autophagosome formation is known to require phosphatidylinositol 3-phosphate (PI(3)P) and occurs near the endoplasmic reticulum (ER), but the exact mechanisms are unknown. We show that double FYVE domain–containing protein 1, a PI(3)P-binding protein with unusual localization on ER and Golgi membranes, translocates in response to amino acid starvation to a punctate compartment partially colocalized with autophagosomal proteins. Translocation is dependent on Vps34 and beclin function. Other PI(3)P-binding probes targeted to the ER show the same starvation-induced translocation that is dependent on PI(3)P formation and recognition. Live imaging experiments show that this punctate compartment forms near Vps34-containing vesicles, is in dynamic equilibrium with the ER, and provides a membrane platform for accumulation of autophagosomal proteins, expansion of autophagosomal membranes, and emergence of fully formed autophagosomes. This PI(3)P-enriched compartment may be involved in autophagosome biogenesis. Its dynamic relationship with the ER is consistent with the idea that the ER may provide important components for autophagosome formation.

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Dynamics and diversity in autophagy mechanisms: lessons from yeast.

Hitoshi Nakatogawa, Kuninori Suzuki, Yoshiaki Kamada … (2009)

Autophagy is a fundamental function of eukaryotic cells and is well conserved from yeast to humans. The most remarkable feature of autophagy is the synthesis of double membrane-bound compartments that sequester materials to be degraded in lytic compartments, a process that seems to be mechanistically distinct from conventional membrane traffic. The discovery of autophagy in yeast and the genetic tractability of this organism have allowed us to identify genes that are responsible for this process, which has led to the explosive growth of this research field seen today. Analyses of autophagy-related (Atg) proteins have unveiled dynamic and diverse aspects of mechanisms that underlie membrane formation during autophagy.

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Author and article information

Contributors

Beth Levine: beth.levine@utsouthwestern.edu

Journal

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date (Electronic): 20 January 2011

Publication date (Print): 2011

Volume: 469

Issue: 7330

Pages: 323-335

Affiliations

[1 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Department of Internal Medicine, , University of Texas Southwestern Medical Center, ; 5323 Harry Hines Boulevard, Dallas, 75390-9113 Texas USA

[2 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Department of Microbiology, , University of Texas Southwestern Medical Center, ; 5323 Harry Hines Boulevard, Dallas, 75390-9113 Texas USA

[3 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, ; 5323 Harry Hines Boulevard, Dallas, 75390-9113 Texas USA

[4 ]GRID grid.265073.5, ISNI 0000 0001 1014 9130, Department of Physiology and Cell Biology, , Tokyo Medical and Dental University, ; 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan

[5 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Pathology and Immunology, , Washington University School of Medicine and Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Campus Box 8118, 660 South Euclid Avenue, Saint Louis, Missouri 63110, USA. virgin@wustl.edu, ; ,

Article

Publisher ID: BFnature09782

DOI: 10.1038/nature09782

PMC ID: 3131688

PubMed ID: 21248839

SO-VID: 5acd2e8a-1c51-4c99-84ce-fec8cae512df

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.