Autophagy in Dictyostelium: Mechanisms, Regulation and Disease in a Simple Biomedical Model
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Autophagy ISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: http://www.tandfonline.com/loi/kaup20 Autophagy in Dictyostelium: Mechanisms, regulation and disease in a simple biomedical model Ana Mesquita, Elena Cardenal-Muñoz, Eunice Dominguez, Sandra Muñoz- Braceras, Beatriz Nuñez-Corcuera, Ben A. Phillips, Luis C. Tábara, Qiuhong Xiong, Roberto Coria, Ludwig Eichinger, Pierre Golstein, Jason S. King, Thierry Soldati, Olivier Vincent & Ricardo Escalante To cite this article: Ana Mesquita, Elena Cardenal-Muñoz, Eunice Dominguez, Sandra Muñoz- Braceras, Beatriz Nuñez-Corcuera, Ben A. Phillips, Luis C. Tábara, Qiuhong Xiong, Roberto Coria, Ludwig Eichinger, Pierre Golstein, Jason S. King, Thierry Soldati, Olivier Vincent & Ricardo Escalante (2017) Autophagy in Dictyostelium: Mechanisms, regulation and disease in a simple biomedical model, Autophagy, 13:1, 24-40, DOI: 10.1080/15548627.2016.1226737 To link to this article: http://dx.doi.org/10.1080/15548627.2016.1226737 View supplementary material Published online: 07 Oct 2016. Submit your article to this journal Article views: 534 View related articles View Crossmark data Citing articles: 3 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kaup20 Download by: [UNAM Ciudad Universitaria] Date: 01 August 2017, At: 08:59 AUTOPHAGY 2017, VOL. 13, NO. 1, 24–40 http://dx.doi.org/10.1080/15548627.2016.1226737 REVIEW Autophagy in Dictyostelium: Mechanisms, regulation and disease in a simple biomedical model Ana Mesquitaa,b, Elena Cardenal-Munoz~ c, Eunice Domingueza,d, Sandra Munoz-Braceras~ a, Beatriz Nunez-Corcuera~ a, Ben A. Phillipse, Luis C. Tabaraa, Qiuhong Xiongf, Roberto Coriad, Ludwig Eichingerf, Pierre Golsteing, Jason S. Kinge, Thierry Soldatic, Olivier Vincenta, and Ricardo Escalantea aInstituto de Investigaciones Biomedicas “Alberto Sols” (CSIC-UAM), Madrid, Spain; bUniversity of Cincinnati College of Medicine, Cincinnati, OH, USA; cDepartment de Biochimie, Faculte des Sciences, Universite de Geneve, Switzerland; dDepartamento de Genetica Molecular, Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico; eDepartment of Biomedical Sciences, University of Sheffield, UK; fCenter for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany; gCentre d’Immunologie de Marseille-Luminy, Aix Marseille Universite UM2, Inserm, U1104, CNRS UMR7280, Marseille, France ABSTRACT ARTICLE HISTORY Autophagy is a fast-moving field with an enormous impact on human health and disease. Understanding Received 6 June 2016 the complexity of the mechanism and regulation of this process often benefits from the use of simple Revised 28 July 2016 experimental models such as the social amoeba Dictyostelium discoideum. Since the publication of the first Accepted 16 August 2016 review describing the potential of D. discoideum in autophagy, significant advances have been made that KEYWORDS demonstrate both the experimental advantages and interest in using this model. Since our previous Atg proteins; autophagic cell review, research in D. discoideum has shed light on the mechanisms that regulate autophagosome death; autophagy; formation and contributed significantly to the study of autophagy-related pathologies. Here, we review Dictyostelium; infection; these advances, as well as the current techniques to monitor autophagy in D. discoideum. The social amoeba comprehensive bioinformatics search of autophagic proteins that was a substantial part of the previous review has not been revisited here except for those aspects that challenged previous predictions such as the composition of the Atg1 complex. In recent years our understanding of, and ability to investigate, autophagy in D. discoideum has evolved significantly and will surely enable and accelerate future research using this model. Introducing D. discoideum, a simple model for autophagy 4 with striking similarities to animal cells diseases, the study of the mechanism of action of certain drugs,5 cancer,6 neurodegenerative disorders7 and lysosomal- Dictyostelium discoideum is a protist that belongs to the Amoe- related disorders8 among others. D. discoideum also provides bozoa, a sister group of animals and fungi. They are known as useful ways to study the mechanisms and the physiological social amoebae since the motile cells are able to aggregate and roles of autophagy.9 As in in other organisms, autophagy is form a simple multicellular organism. Under starvation, groups required for D. discoideum to survive starvation, for the turn- of approximately 100,000 cells form a mound that goes through over of proteins, to remove protein aggregates and is also different stages of development to give rise to a fruiting body, in fundamental during infection by intracellular pathogens. The Downloaded by [UNAM Ciudad Universitaria] at 08:59 01 August 2017 which vacuolated dead cells form a stalk that supports the first description of autophagic vacuoles in D. discoideum spores (Fig. 1). Vegetative D. discoideum cells are more similar (defined at that time simply as “bodies containing partially to animal cells than fungi or plant cells in many respects. For degraded cytoplasmic material”) comes from transmission elec- example, they lack rigid cell walls that might restrict movement, tron microscopy (TEM) studies of germinating spores in allowing the cells to perform typical animal-like processes such 1969,10 shortly after Christian de Duve coined the term as phagocytosis, macropinocytosis, pseudopod-based cell autophagy.11 We have come a long way from these initial mor- motility and chemotaxis. The parallels with animal cells phological observations and now begin to understand the extends to the evolutionary conservation of many genes that significance and the mechanisms of this crucial cellular process have been lost during fungal evolution.1 in the context of a whole organism. The similarity to animal cells makes D. discoideum a suitable During starvation, autophagy is responsible for the libera- model to address the study of genes or processes relevant to tion of nutrients to maintain viability. Therefore, defects in human disease. These include the study of pathogen infec- autophagy drastically reduce the ability of cells to survive tions,2 cell motility-related pathologies,3 mitochondrial prolonged periods of nutrient deprivation. Typically, wild-type CONTACT Ricardo Escalante [email protected] Arturo Duperier 4. 28029-Madrid, Spain Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kaup. Supplemental data for this article can be accessed on the publisher’s website. © 2017 Taylor & Francis AUTOPHAGY 25 Figure 1. D. discoideum’s life cycle and representative phenotypes associated with the lack of autophagy. Mutant strains have been described for the genes depicted at the right side (see details in the main text). The pictures correspond from top to bottom to the strains DDB_G0269162¡/atg13¡, tipC¡ and wild-type AX4. D. discoideum cells survive for more than 10 d under amino Although autophagy was initially thought to simply be a mech- acid starvation, whereas autophagy-deficient mutants start los- anism to recycle nutrients by nonselective self-degradation (so ing viability after just 24 h.12,13 During starvation, autophagy is called bulk autophagy), the enormous importance of selective also responsible for a reduction in both cell volume and total autophagy is now becoming clear. The selective process is protein.12,13 The D. discoideum developmental program takes devoted to the specific degradation of abnormal protein aggre- place in the absence of nutrients; therefore, the intracellular gates (aggrephagy), organelles (mitophagy, pexophagy, riboph- degradation and recycling of the cells own material by auto- agy, reticulophagy, nucleophagy) or pathogens (xenophagy). phagy becomes essential as a source of energy and simple Impaired selective autophagy is therefore thought to underlie metabolites required for the biosynthetic pathways taking place the etiology of numerous diseases.18 during development. Thus, it is not surprising that autophagic The hallmark of autophagy is the formation of intracellular dysfunction leads to abnormal development, which facilitates double-membrane vesicles (autophagosomes), which eventually the identification of autophagy mutants in the laboratory. The fuse with lysosomes, leading to degradation of the cargo and severity of the phenotype ranges from complete lack of aggre- the inner membrane. The basic molecular machinery that con- gation to the formation of multi-tipped mounds, which are trols autophagy was initially discovered in Saccharomyces cere- Downloaded by [UNAM Ciudad Universitaria] at 08:59 01 August 2017 unable to form normal stalks and viable spores (Fig. 1).13 It is visiae, in which the proteins involved were named Atg, for unclear how much of the defects in development are simply the autophagy-related. These proteins form different complexes result of imbalanced nutrient homeostasis or whether more that are required for the induction, elongation and completion specific signaling events are involved. However, the signaling of the autophagic process. This has been extensively reviewed peptide SDF-2 (spore differentiation factor 2) is essential for in the past few years.19-21 Most of these proteins and complexes spore formation, and its precursor protein, AcbA, is secreted by can be recognized in D. discoideum by sequence