Conserved autophagy genes in yeast, nematodes, flies, and mammals.
Abstract
Autophagy is an evolutionarily conserved process utilized by most organisms to clear cellular damage and recycle building blocks for energy production. In this chapter, we emphasize the importance of genetic model organisms, including yeast, nematodes, flies, and mammals in the discovery and understanding of the autophagy process. We highlight the important roles of autophagy in aging, stress tolerance, neuronal health, organismal development, and pathogen resistance in invertebrate and vertebrate model organisms. We provide examples on how the same autophagy‐related pathways that increase stress response and longevity in lower organisms could be utilized by cancer cells to survive harsh microenvironments, proliferate, and metastasize, with emphasis on the dual role of autophagy in cancer: an antitumorigenic or a protumorigenic process.
Keywords
- autophagy
- model organisms
- stress tolerance
- aging
- organismal development
- cancer
1. Introduction to autophagy
Autophagy is an evolutionarily conserved “self‐degradation” process through which cytosolic compartments and organelles are delivered to the lysosome for degradation [1]. Autophagy exists in three forms: microautophagy where cytosolic components are directly engulfed in lysosomes, chaperone‐mediated autophagy through which designated proteins are selectively targeted to the lysosomes, and macroautophagy (noted herein as autophagy) where cytosolic material is enclosed in a double‐membrane autophagosomal structure that is delivered to lysosomes for degradation by acidic hydrolases [1]. Autophagy is selectively activated to remove cellular damage or is non‐selectively activated under stress situations to supply energy and sustain cellular/organismal viability.
The autophagy machinery components and the physiology of this process are highly conserved across evolution from yeast to mammals. The autophagy‐related genes (ATGs) have been initially identified in yeast
Yeasts | Mammals | |||
---|---|---|---|---|
Regulation of induction | yTOR | dTOR | ||
Snf1 | AMPK | |||
Atg1/ULK autophagy initiation complex |
Atg1 | Atg1 | ||
Atg13 | Atg13 | |||
Fip200 | Fip200 | |||
Atg101 | epg‐9 | Atg101 | ||
Class III PI3K complex | Vps34 | Vps34 | ||
Vps15 | Vps15 | |||
Atg6 | Atg6 | |||
Atg14 | Atg14 | |||
Atg2‐Atg18 conjugation complex |
Atg2 | Atg2 | ||
Atg18 | Atg18a, Atg18b | |||
Atg 9 transmembrane | Atg9 | Atg9 | ||
Atg12 conjugation system | Atg12 | Atg12 | ||
Atg5 | Atg5 | |||
Atg10 | Atg10 | |||
Atg16 | Atg16 | |||
Atg7 | Atg7 | |||
Atg8 conjugation system | Atg8 | Atg8a, Atg8b | ||
Atg3 | Atg3 | |||
Atg4 | Atg4a, Atg4b | |||
Atg7 | Atg7 |
This review focuses on the multifaceted roles of autophagy in model organisms and how these conserved pathways could be adopted by cancer cells to suppress or promote tumorigenesis.
2. The importance of invertebrate model organisms
Although mammalian model organisms such as mice and rats are highly advantageous to study disease‐related biological processes in humans due to the close anatomical and physiological similarities between systems, they have disadvantages including space, cost, and time‐consuming transgenic technologies. Yeast models including budding yeast
First, yeasts, flies, and nematodes are characterized by their short lifespans and rapid reproductive lifecycles. Second, their genomes are fully sequenced [13–15] and well annotated, and a large number of tools and resources are available in accessible bioinformatics databases specific to every model (Yeast:
Although autophagy has been first observed by electron microscopy in mammalian cells in the 1950s [16], more than 30 autophagy genes have been discovered using genetic screens in yeast, and many of them have homologues in humans [2–7]. The rapid reproductive life cycles and short lifespans, the massive generation of tools to study autophagy, and the ease with which researchers pursue genetics work
Despite the large advantages of invertebrate model organisms, they also have many limitations. The anatomy and physiology of the organismal systems, including immune, circulatory, respiratory, and nervous systems, largely differ from that of humans. Therefore, the importance of mammalian
3. Methods to monitor autophagy in model organisms
Similar methods to study autophagy have been used in invertebrate model organisms and mammalian systems with the employment of the benefits of every system. These methods are recently reviewed in detail for yeast [17–20],
Despite its complexity and difficulty to pursue, electron microscopy is one of the most reliable methods to visualize autophagic structures and has been used to monitor autophagy in many model organisms. However, since it requires a substantial specialized expertise, most researchers currently rely on light microscopic and biochemical methods, which are more accessible and easier to perform in most organisms. The fluorescent image analysis of autophagic components using reporters of tagged autophagic proteins has been widely used. LC3/ATG8 exists in two forms: LC3‐I is cytosolic and soluble, and LC3‐II is conjugated with phosphatidylethanolamine and is bound to the autophagosomal membranes. When autophagy is induced, the conjugation reaction can be monitored using the LC3:GFP reporter and the change between the diffuse localization of LC3 into autophagosomal puncta structures reflects the autophagic activity. This reporter is one of the most popular with its orthologues in
Since autophagic proteins also accumulate upon defective autophagy, researchers have monitored the degradation of cargo proteins such as p62 in most model organisms as well [24, 25, 28, 41, 42]. Furthermore, autophagy inhibitors have been used to determine whether the accumulation of autophagosomes is due to impaired autophagy or to a heightened autophagic flux. The most recent studies employ the mRFP‐GFP‐LC3, which enables the distinction between heightened autophagic flux and impaired autophagy. In this method, mCherry and GFP have been used as red and green fluorescent protein markers, respectively, to trace the autophagic protein LC3. Upon physiological pH in newly formed autophagosomes or when autophagy is impaired, both GFP and mCherry colocalize in puncta leading to yellow puncta structures, whereas upon lysosomal fusion and acidification, the GFP signal is lost and only mCherry is detected.
High‐resolution live‐cell imaging to visualize the dynamics of autophagy has been also employed and reviewed in detail [36].
4. Autophagy‐related biological roles in model organisms
Despite the anatomical, morphological, and physiological differences between model organisms, autophagy appears to play similar important roles across evolution. In this section, we review the major autophagy‐associated roles at the cellular and organismal levels in invertebrate and mammalian model systems.
4.1. Stress tolerance
In most organisms, autophagy is activated by different stresses including nutrient deprivation, oxidative stress, hypoxia, temperature shifts, and others, to eliminate damaged macromolecules and to produce energy
In yeast, mutation of
In
The role of autophagy in stress resistance has been demonstrated not only in invertebrate models but also with mammalian cell culture and
4.2. Extension of lifespan
Accumulating evidence demonstrates that longevity pathways converge on autophagic processes in many organisms to regulate diverse cellular functions including the clearance of damaged proteins and organelles and the remodeling of cellular metabolism. In
HLH‐30 is the worm homologue of transcription factor EB (TFEB), a master transcriptional regulator of lysosomal and autophagic pathways [67, 68]. The overexpression of HLH‐30 increases lifespan in
In
In yeast, the role of autophagy in aging seems to be context‐dependent. Autophagy has been shown to be required for the extension of chronological lifespan by low doses of the mammalian target of rapamycin (mTOR) inhibitor rapamycin [72, 73], methionine limitation [74], and calorie restriction [75]. In contrast, Tang et al., 2008 claim that autophagy genes may be required or not for the lifespan extension by calorie restriction depending on their role in the autophagy process. Specifically, they show that the deletion of genes involved in autophagosome formation including
In mammals, the link between autophagy and the organismal extension of lifespan has not been clearly established. A few studies support the role of autophagy in promoting longevity in mammals. For instance, ATG5 overexpression has been shown to extend lifespan by 17.2% in mice [54]. Interestingly, rapamycin feeding of mice at their old age extends their lifespan, which could be due to autophagy activation [77]. While rapamycin is a strong mTOR inhibitor and autophagy inducer, the link between rapamycin feeding and increased autophagy has not been made, and therefore, the extension of lifespan by administration of rapamycin in mice may not be due to autophagy activation per se but to other mechanisms [77].
Although the role of autophagy in mammalian organismal lifespan is still not clearly elucidated, many studies demonstrate an important role for autophagy in delaying the acquisition of aging features of multiple cells and tissues. Numerous studies also claim a decline in the autophagic activity in many mammalian organs upon aging [78–83]. For example, autophagy genes
4.3. Resistance to pathogen infection
The induction of autophagy has been widely shown to contribute to the organismal survival to infection with pathogens. In
In
The transcriptional upregulation of autophagy genes by TFEB has been also associated with increased resistance to pathogens. Upon infection with
How autophagy mediates resistance to pathogens is still not clear. Xenophagy (eating the pathogen) is a cellular defense mechanism through which cells direct autophagy to degrade the invading pathogens. Autophagy genes restrict
In mammalian cells, autophagy also plays an essential role in the protection against invading pathogens, including
4.4. Organismal development
Accumulating evidence highlights an important role for autophagy during organismal development. Deletion of autophagy genes leads to severe defects and causes early lethality in many organisms. For example,
In mice,
The discovery that autophagy is involved in the degradation of the paternal mitochondria is another important aspect during development. In most eukaryotes, the maternal mitochondrial genome is believed to be the one inherited and thus the degradation of the sperm‐inherited mitochondrial genome is essential. In
4.5. Neuronal health
The accumulation of autophagosomes has been observed in the neurons of individuals affected with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Autophagy improves neuronal health by degrading damaged proteins, specifically mutant proteins associated with neurological disorders and toxic aggregation‐prone proteins [88, 91, 126–128]. Non‐mammalian model systems are excellent to study protein homeostasis in regard to fatal neurological disorders.
In addition, C. elegans [129–133] and flies [134–139] researchers have generated transgenic animals that express polyglutamine repeats, beta-amyloid peptides, and the αsynuclein protein, to mimic the pathologies of Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease, respectively.
Using electron microscopy and the LGG‐1:GFP reporter, the expression of human beta‐amyloid (1–42) in
In
Consistently with what has been observed in
Numerous studies highlight an important role for autophagy in mammalian neurogenesis and neuronal “maintenance.” Several neurological disorders in humans are associated with impaired autophagy and defects in the clearance of damaged organelles and proteins [154, 155]. Among several examples, mutations in
4.6. Autophagic cell death and clearance of cellular corpses
Apoptosis or programmed cell death is a fundamental component in the development of
In
In mice, autophagy contributes to the programmed cell death‐mediated clearance of apoptotic cell corpses. Lack of
4.7. Metabolism
In invertebrates, the storage and biosynthesis of energy reserves, including yolk particles, lipids, and glycogen, play a crucial role in development during early embryogenesis and later during adulthood [178]. In
The role of autophagy in lipid metabolism has been reported in many organisms. In
Following stress and energy depletion, the mobilization of “energy‐rich” intracellular contents is essential. The autophagic degradation of lipids has been reported throughout evolution. In contrast to what has been observed in
In accordance with the role of autophagy in lipid metabolism, autophagy also plays an important role in glycogen metabolism. In
5. From model organisms to cancer in humans
Genetic pathways that alter autophagy in model organisms are often linked to cancer in humans. For instance, AMPK, TOR, Insulin, SKN‐1/NRF2, CEP‐1/p53, FLCN‐1, and other signaling pathways modulate autophagy in model organisms and are associated with cancer initiation and progression in humans. Two major kinases are important in stress sensing and autophagy regulation: the mammalian target of rapamycin (mTOR) and the 5′ AMP‐activated protein kinase (AMPK). TOR is a serine/threonine kinase that is activated during nutrient‐rich conditions and is inhibited by starvation. In
Autophagy deregulation has been widely reported in human cancers. This is reviewed in detail in Refs. [202, 203]. Whether autophagy plays a tumor‐suppressing role or a tumor‐promoting role is still controversial since both cases have been reported. Although autophagy protects against tumorigenesis since it plays a central role in the clearance of damaged cellular macromolecules and organelles, increasing evidence suggests that autophagy could also acquire tumor‐promoting functions. By supplying cancer cells with energy, autophagy may promote their survival because they are often exposed to nutrient deprivation and hypoxia due to lack of blood vessels.
5.1. Autophagy as a tumor‐suppressing mechanism
The observation that autophagy gene ATG6/BECN1 is monoallelically lost in a large number of prostate, breast, and ovarian cancers supported the tumor suppression role of autophagy at first [117, 204–206]. Consistently, autophagy genes are frequently downregulated in tumors. In mice, homozygous deletion of
How autophagy acts as a tumor suppressor is not clear yet. A plausible explanation could be that loss of autophagy increases oxidative stress, which leads to the accumulation of damaged macromolecular cellular components [209, 210]. This is supported by the fact that impaired autophagy increases genomic instability presumably through lack of degradation of damaged mitochondria and an intracellular increase in the levels of reactive oxygen species (ROS) [211, 212]. The selective degradation of damaged mitochondria by autophagy has been shown to protect against oxidative stress and mitochondrial dysfunction [213]. Autophagy deficiency has been shown to contribute to the tumorigenesis induced by oncogene activation or by chemical carcinogens. Deletion of
Autophagy has been recently shown to mediate cellular senescence through the degradation of nuclear lamina upon oncogenic events, suggesting that this guardian role of autophagy might prevent tumorigenesis [216].
5.2. Autophagy as a tumor‐promoting mechanism
The balance between autophagy and apoptosis is a key factor in the cellular decision between life and death. These two pathways are connected, and deregulation in this balance is a main factor in carcinogenesis. Upon cellular exposure to stress, when the damage cannot be repaired, cells normally undergo programmed cell death to eliminate them. When cells escape these control mechanisms and are unable to die, resistant clones emerge which could lead to cancer. Therefore, mechanisms of resistance to stress are often utilized by cancer cells to survive and proliferate. Autophagy is induced in hypoxic and highly nutrient‐stressed tumor microenvironments [211, 212]. Autophagy is also required to promote tumorigenesis by activating mutations of multiple oncogenes, including
The role of P62/SQSTM1 in tumorigenesis is controversial and context‐dependent. While autophagy suppresses tumorigenesis by eliminating P62, recent findings demonstrate that P62 synergizes with autophagy to promote tumor growth
Several tumor suppressor genes are associated with aberrant autophagic flux. Mutation in the tumor suppressor gene
Autophagy also plays a critical role in sustaining cancer cell viability and promoting tumor growth in pancreatic ductal adenocarcinoma [228]. MiT/TFE‐dependent transcriptional activation of the lysosomal‐autophagic pathway is essential for metabolic reprogramming in pancreatic ductal adenocarcinomas and drives aggressive malignancies [229].
6. Conclusion and perspectives
The autophagy‐associated pathways that alter lifespan, stress tolerance, neuronal health, resistance to pathogens, and metabolism in lower organisms are highly evolutionarily conserved and are associated with tumorigenesis in mammals. Although the autophagic process does not change between cells/tissues/organisms, its roles are diverse and depend on the context. The important role of autophagy as a “guardian” of cellular integrity by clearing damaged components helps protect organisms against many diseases, including neurological disorders and cancer. Moreover, the important role of autophagy in energy supply and survival to harsh environmental conditions could be employed by cancer cells to survive hypoxic tumor microenvironments. Due to the fact that the molecular and functional basis of autophagic processes are highly conserved between organisms, it is of great interest to use these organisms to link autophagy to important disease‐associated signaling pathways. Finding pathways that alter autophagic activities is essential and could help the development of cures for multiple diseases with the common denominator: autophagy. Performing such assays in invertebrate models is an advantageous fast, inexpensive, and a reliable method that has great potential and value for the understanding and treatment of human diseases linked to autophagy including cancer.
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