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    Discovery of Atg5/Atg7-independent alternative macroautophagy (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-02
    Description: Macroautophagy is a process that leads to the bulk degradation of subcellular constituents by producing autophagosomes/autolysosomes. It is believed that Atg5 (ref. 4) and Atg7 (ref. 5) are essential genes for mammalian macroautophagy. Here we show, however, that mouse cells lacking Atg5 or Atg7 can still form autophagosomes/autolysosomes and perform autophagy-mediated protein degradation when subjected to certain stressors. Although lipidation of the microtubule-associated protein light chain 3 (LC3, also known as Map1lc3a) to form LC3-II is generally considered to be a good indicator of macroautophagy, it did not occur during the Atg5/Atg7-independent alternative process of macroautophagy. We also found that this alternative process of macroautophagy was regulated by several autophagic proteins, including Unc-51-like kinase 1 (Ulk1) and beclin 1. Unlike conventional macroautophagy, autophagosomes seemed to be generated in a Rab9-dependent manner by the fusion of isolation membranes with vesicles derived from the trans-Golgi and late endosomes. In vivo, Atg5-independent alternative macroautophagy was detected in several embryonic tissues. It also had a function in clearing mitochondria during erythroid maturation. These results indicate that mammalian macroautophagy can occur through at least two different pathways: an Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nishida, Yuya -- Arakawa, Satoko -- Fujitani, Kenji -- Yamaguchi, Hirofumi -- Mizuta, Takeshi -- Kanaseki, Toku -- Komatsu, Masaaki -- Otsu, Kinya -- Tsujimoto, Yoshihide -- Shimizu, Shigeomi -- England -- Nature. 2009 Oct 1;461(7264):654-8. doi: 10.1038/nature08455.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794493" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/drug effects/*physiology ; Etoposide/pharmacology ; Fibroblasts/cytology/drug effects/metabolism ; Food Deprivation ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins/*deficiency/genetics/metabolism ; Phagosomes/drug effects/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; rab GTP-Binding Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-04-27
    Description: Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes. Here we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts showed infiltration of inflammatory cells and increased messenger RNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9 ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378041/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378041/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oka, Takafumi -- Hikoso, Shungo -- Yamaguchi, Osamu -- Taneike, Manabu -- Takeda, Toshihiro -- Tamai, Takahito -- Oyabu, Jota -- Murakawa, Tomokazu -- Nakayama, Hiroyuki -- Nishida, Kazuhiko -- Akira, Shizuo -- Yamamoto, Akitsugu -- Komuro, Issei -- Otsu, Kinya -- CH/11/3/29051/British Heart Foundation/United Kingdom -- RG/11/12/29052/British Heart Foundation/United Kingdom -- England -- Nature. 2012 May 10;485(7397):251-5. doi: 10.1038/nature10992.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22535248" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Aorta/pathology ; *Autophagy ; Cardiomegaly/etiology ; Constriction, Pathologic/complications ; Cytokines/genetics ; DNA, Mitochondrial/*immunology/*metabolism ; Endodeoxyribonucleases/deficiency/genetics/metabolism ; Heart/physiopathology ; Heart Failure/*etiology/immunology/metabolism/*pathology ; Lysosomes/enzymology/metabolism ; Male ; Mice ; Mitochondria ; Myocarditis/*etiology/*immunology/metabolism/pathology ; Myocardium/pathology ; Myocytes, Cardiac/metabolism/pathology ; Pressure ; RNA, Messenger/genetics/metabolism ; Signal Transduction ; Toll-Like Receptor 9/antagonists & inhibitors/deficiency/immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
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