Autophagy: Nobel Prize 2016 and allergy and asthma research
Authors: Harald Renz
Journal: Journal of Allergy and Clinical Immunology (2017)

The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi, Professor at the Tokyo Institute of Technology, for "recycling." Recycling on the cellular level is termed autophagy and is a fundamental process for degrading and recycling cellular components. It is now well regarded that this process plays an important role not only in physiologic cellular homeostasis but also in a variety of diseases. The story starts about 60 years ago with the discovery of the lysosome. Lysosomes are specialized organelles containing enzymes that digest proteins, carbohydrates, and lipids. For the discovery of this process, Christian de Duve, a Belgian scientist, was awarded the Nobel Prize in Physiology or Medicine in 1974. The next important step in this journey was the observation that under certain conditions large cellular components and sometimes whole organelles can be found inside lysosomes. A new type of vesicle was discovered and named autophagosomes, describing a process of "self-eating" to understand the mechanism of how such large cargos get into the lysosome. A few years later, researchers discovered an additional system to degrade proteins, although not as large "fragments" but rather one by one (Fig 1). This system was termed the proteasome, and Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize in Chemistry in 2004 for the discovery of ubiquitin-mediated protein degradation (Table I).Table IKey discoveries on the journey to the autophagosome1955Lysosomesde Duve1966Function of lysosome ("autophagy")de Duve1968AutophagosomeArstila, Trump1979ProteasomeHarshko, Chiecanova, Rose1980UbiquitinWilkinson, Urban, Haas1992Autophagosome as machinery of autophagyOhsumi1993The first autophagy gene, ATG1Ohsumi Open table in a new tab Ohsumi and colleagues now discovered many steps and the molecular tools involved in this complex process of recycling.1Tsukada M. Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae.FEBS Lett. 1993; 333: 169-174Crossref PubMed Scopus (1500) Google Scholar, 2Takeshige K. Baba M. Tsuboi S. Noda T. Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction.J Cell Biol. 1992; 119: 301-311Crossref PubMed Scopus (995) Google Scholar, 3Mizushima N. Noda T. Yoshimori T. Tanaka Y. Ishii T. George M.D. et al.A protein conjugation system essential for autophagy.Nature. 1998; 395: 395-398Crossref PubMed Scopus (1351) Google Scholar, 4Ichimura Y. Kirisako T. Takao T. Satomi Y. Shimonishi Y. Ishihara N. et al.A ubiquitin-like system mediates protein lipidation.Nature. 2000; 408: 488-492Crossref PubMed Scopus (1638) Google Scholar He recognized that external cellular stress, such as heat, radiation, starvation, and infection, turn on the cellular recycling machinery to promote survival of the cells. Today, more than 14,000 proteins have been catalogued, among them about 3 dozen proteins involved in autophagy and 113 regulators involved in recycling of survival-eminent materials. Ohsumi and colleagues conducted a series of brilliant experiments in the early 1990s using the bakers' yeast Saccharomyces cerevisiae to identify the essential genes for this process. Through random mutation, he knocked out one after the other of these relevant genes and elucidated the underlying mechanism for autophagy. Through this process, he discovered 15 genes, originally termed autophagy-related genes (ATS) ATG1 to ATG15 and today renamed ATG genes. Today, a disturbed process of autophagy has been linked to many diseases, including Parkinson disease, type II diabetes, Alzheimer disease, certain cancers, and many infections. Furthermore, this process also regulates our own appetite. The process starts in certain neurons in the hypothalamus, where, under starvation conditions, mediators are produced under the control of autophagy. These mediators then trigger our appetite. Recent data indicate that autophagy plays an important role in the inflammatory pathways in allergy and asthma. In this issue of the Journal Radonjic-Hoesli et al5Radonjic-Hoesli S. Wang X. de Graauw E. Stoeckle C. Styp-Rekowska B. Hlushchuk R. et al.Eosinophil cytolysis requires the RIPK3-MLKL signaling pathway and is counter-regulated by autophagy.J Allergy Clin Immunol. 2017; 140: 1632-1642Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar investigate a mechanism that leads to release of cytotoxic granules from eosinophils. Cytolysis is one of these mechanisms and leads to the release of intragranules, so-termed clusters of eosinophil granules. The investigators used state-of-the-art technologies, including time-lapse fluorescence microscopy, electron microscopy, and immunohistochemistry, to prove that cytoplasmic membrane disintegration and intragranule release depend on a signaling pathway, including receptor-interacting protein kinase 3 and mixed lineage kinase-like protein. Importantly, if they activate autophagy in eosinophils, this counterregulates eosinophil cytolysis. Therefore the authors not only demonstrate in a very elegant fashion a new pathway for eosinophil cytolysis, they were also able to link cytolysis with counterregulating autophagy and open new pathways for at least experimental intervention. Autophagy has also been previously linked to the pathogenesis of asthma. Although little work has been carried out in this regard thus far, there are convincing data available linking autophagy in airway epithelium, and autophagy might be essential for bronchial epithelial mucus secretion, as has been shown in an allergic asthma model. Interestingly, autophagy, rather than endoplasmic reticulum stress, contributed to IL-13–induced eotaxin-3 peptide secretion also from human airway epithelial cells.6Ban G.Y. Pham D.L. Trinh T.H. Lee S.I. Suh D.H. Yang E.M. et al.Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target.Clin Exp Allergy. 2016; 46: 48-59Crossref PubMed Scopus (78) Google Scholar, 7Dickinson J.D. Alevy Y. Malvin N.P. Patel K.K. Gunsten S.P. Holtzman M.J. et al.IL13 activates autophagy to regulate secretion in airway epithelial cells.Autophagy. 2016; 12: 397-409Crossref PubMed Scopus (123) Google Scholar, 8Zeki A.A. Ott S. Sandhu K. Ghavami S. Kenyon N.J. The complex roles of endoplasmic reticulum stress and autophagy in modulating Eotaxin-3 production and secretion from human airway epithelial cells.Am J Respir Crit Care Med. 2014; 189: A5683Google Scholar A link between the epithelial-mesenchymal transition unit and autophagy has been shown in other models of allergic asthma.9Cao Z. Pan P. Tan H. Tan Q. Wang Z. Su X. et al.Anti-nerve growth factor antibody reduces airway hyperresponsiveness in a mouse model of asthma by down-regulating the level of autophagy in lungs.Zhonghua Jie He He Hu Xi Za Zhi. 2014; 37: 507-511PubMed Google Scholar, 10Cho I.-H. Choi Y.J. Gong J.H. Shin D. Kang M.K. Kang Y.H. Astragalin inhibits autophagy-associated airway epithelial fibrosis.Respir Res. 2015; 16: 51Crossref PubMed Scopus (62) Google Scholar A further link between autophagy and asthma has been established for human rhinovirus, respiratory syncytial virus, coronavirus, adenovirus, and influenza A virus through the role of autophagy in the defense against respiratory tract viruses, which represent a major exacerbation factor for asthma. In this regard autophagy impairs viral replication, and autophagy is enhanced in the airways of asthmatic patients.11Zhou Z. Jiang X. Liu D. Fan Z. Hu X. Yan J. et al.Autophagy is involved in influenza A virus replication.Autophagy. 2009; 5: 321-328Crossref PubMed Scopus (216) Google Scholar, 12Gannage M. Dormann D. Albrecht R. Dengjel J. Torossi T. Rämer P.C. et al.Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes.Cell Host Microbe. 2009; 6: 367-380Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar Finally, a single nucleotide polymorphism has been discovered in the ATG5 gene, which is one of the genes regulating autophagy. This polymorphism was associated with asthma and low FEV1 levels.13Poon A.H. Chouiali F. Tse S.M. Litonjua A.A. Hussain S.N. Baglole C.J. et al.Genetic and histologic evidence for autophagy in asthma pathogenesis.J Allergy Clin Immunol. 2012; 129: 569-571Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar ATG5 transcripts are enhanced in nasal epithelial cells in patients with acute asthma exacerbations. This could further strengthen the functional link between autophagy and asthma (exacerbation). In summary, the study of autophagy opens a new field in allergy and asthma research. Autophagy is a key process involved in immune responses, inflammation, and antiviral immunity. Further studies are warranted to establish this link and also, more importantly, to explore the possibilities of therapeutic intervention in this regard. We are looking forward to reading more articles about autophagy, allergy, and inflammation in the Journal. Adhesion-induced eosinophil cytolysis requires the receptor-interacting protein kinase 3 (RIPK3)–mixed lineage kinase-like (MLKL) signaling pathway, which is counterregulated by autophagyJournal of Allergy and Clinical ImmunologyVol. 140Issue 6PreviewEosinophils are a subset of granulocytes that can be involved in the pathogenesis of different diseases, including allergy. Their effector functions are closely linked to their cytotoxic granule proteins. Release takes place through several different mechanisms, one of which is cytolysis, which is associated with release of intact granules, so-called clusters of free eosinophil granules. The mechanism underlying this activation-induced form of cell death in eosinophils has remained unclear. Full-Text PDF