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      Autophagy-Independent Functions of the Autophagy Machinery

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          Abstract

          Macroautophagy (herein referred to as autophagy) is an evolutionary ancient mechanism that culminates with the lysosomal degradation of superfluous or potentially dangerous cytosolic entities. Over the past 2 decades, the molecular mechanisms underlying several variants of autophagy have been characterized in detail. Accumulating evidence suggests that most, if not all, components of the molecular machinery for autophagy also mediate autophagy-independent functions. Here, we discuss emerging data on the non-autophagic functions of autophagy-relevant proteins.

          Abstract

          Proteins that regulate macroautophagy mediate a number of non-autophagy roles in physiology and disease.

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          Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

          Joseph D. Mancias, Xiaoxu Wang, Steven P. Gygi … (2014)
          Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration 1,2 . Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo including organelles, proteins, or intracellular pathogens are targeted for selective autophagy is limited 3 . We employed quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors. Like known cargo receptors, NCOA4 was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species 4 but is degraded via autophagy to release iron 5,6 through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.
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            Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

            Zhenyu Yue, Shengkan Jin, Chingwen Yang … (2003)
            The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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              Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.

              Congcong He, Michael C. Bassik, Viviana Moresi … (2012)
              Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
              Article 0 comments Cited 414 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Lorenzo Galluzzi
                Douglas R. Green
                Journal
                Journal ID (nlm-ta): Cell
                Journal ID (iso-abbrev): Cell
                Title: Cell
                Publisher: Elsevier Inc.
                ISSN (Print): 0092-8674
                ISSN (Electronic): 1097-4172
                Publication date PMC-release: 13 June 2019
                Publication date (Print): 13 June 2019
                Publication date (Electronic): 13 June 2019
                Volume: 177
                Issue: 7
                Pages: 1682-1699
                Affiliations
                [1 ]Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
                [2 ]Sandra and Edward Meyer Cancer Center, New York, NY, USA
                [3 ]Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
                [4 ]Université Paris Descartes/Paris V, Paris, France
                [5 ]Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
                Author notes
                [∗ ]Corresponding author deadoc80@ 123456gmail.com
                [∗∗ ]Corresponding author douglas.green@ 123456stjude.org
                Article
                Publisher ID: S0092-8674(19)30554-9
                DOI: 10.1016/j.cell.2019.05.026
                PMC ID: 7173070
                PubMed ID: 31199916
                SO-VID: 89ceb9cc-e752-4b44-8571-9142e3b5ce9c
                Copyright © © 2019 Elsevier Inc.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: atg5,becn1,lc3-associated phagocytosis,proliferation,regulated cell death,vesicular trafficking
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: atg5, becn1, lc3-associated phagocytosis, proliferation, regulated cell death, vesicular trafficking

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