General features of
Schizosaccharomyces pombe (Sz. pombe), or fission yeast, is an ascomycete unicellular fungus that has been used as a model system for studying diverse biological processes of higher eukaryotic cells, such as the cell cycle and the maintenance of cell shape, apoptosis, and ageing. Sz. pombe is a rod-shaped cell that grows by apical extension; it divides along the long axis by medial fission and septation. The fission yeast has a doubling time of 2–4 hours, it is easy and inexpensive to grow in simple culture conditions, and can be maintained in the haploid or the diploid state. Sz. pombe can be genetically manipulated using methods such as mutagenesis or gene disruption by homologous recombination. Fission yeast was defined as a micro-mammal because it shares many molecular, genetic, and biochemical features with cells of higher eukaryotes in mRNA splicing, post-translational modifications as N-glycosylation protein, cell-cycle regulation, nutrient-sensing pathways as the target of rapamycin (TOR) network, cAMP-PKA pathway, and autophagy. This chapter uses Sz. pombe as a useful model for studying important cellular processes that support life such as autophagy, apoptosis, and the ageing process. Therefore, the molecular analysis of these processes in fission yeast has the potential to generate new knowledge that could be applied to higher eukaryotes.
- Schizosaccharomyces pombe
- cellular model
- chronological lifespan
1.1. General features of
1.2. Genome organization of
The whole genome of
2. Mating-type locus, heterothallic, and homothallic phenotype
The heterothallic strain with only one mating type, are able to mate with heterothallic
|Doubling time of 2–4 hours|
3–4 μm in diameter and 7–14 μm in length
Ascospores arranged linearly
Easy genetic manipulation and mutant generation
|NCBI Taxonomy ID: 284812|
|Phase||Percentage in the full cell cycle|
|Fission yeast can exist stably in either haploid or diploid states.|
|Gene density||Coding (%)|
|Chromosome||5.7||2483||58.6||Centromere I 35 kb|
|Chromosome||4.6||2457||57.5||Centromere II 65 kb|
|Chromosome||3.5||2790||54.5||Centromere III 110 kb|
|Mitochondrial genome||20 kb|
|Count of known and putative peptidases121|
non-peptidase homologues 39
3. Cell cycle of
4. Cellular process studied using
Fission yeast presents a short cell cycle and is easy to manipulate by genetic classical and molecular analysis.
4.1. Model for studying the eukaryotic cell cycle
4.2. Cellular ageing
The identification of evolutionarily conserved mechanisms that determine long lifespans has been of great interest, making the fission yeast
Autophagy is a catabolic mechanism that regulates the intracellular turnover of unfolded/misfolded, long-lived, or damaged proteins, lipids, and organelles (such as mitochondria and the endoplasmic reticulum (ER), through its sequestration within a double-membrane and delivery to lysosomes for degradation and recycling of biocomponents. Under basal conditions, autophagy is a housekeeping programme, but it can also be activated by nutrient starvation, low cellular energy levels, amino acid deprivation, growth factor withdrawal, ER stress, hypoxia, oxidative stress, and infection [50–54]. Autophagy deregulation in higher eukaryotes leads to muscle atrophy, myopathy, and cardiac and immune disease [52–54], and plays a dual role in the pathogenesis of cancer [50, 52, 55, 56].
Duve  introduced the term autophagy from the Greek
The Atg machinery was classified into five groups according to function in each step of the autophagic process (Table 2 and Figure 3) [1–6, 11, 12, 50–55, 60, 63, 64]: ULK1 kinase and its regulators that signal the autophagosome biogenesis, the phosphatidylinositol (PtdIns) 3- kinase complex controls the nucleation step that recruitsother Atg proteins hierarchically, the elongation of the phagophore mediated by the Atg12 and LC3 conjugation systems, and a subgroup of proteins with unknown functions. In mammals under nutrient rich conditions, insulin or growth factors activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. When PI3K is activated, it converts phosphatidylinositol (3, 4)-bis phosphate (PIP2) to phosphatidylinositol-3 phosphate (PIP3), then Akt is activated and inactivated by phosphorylation to TSC which leads to mTOR complex 1 (mTORC1) activation. mTORC1 negatively regulates ULK1 and Atg13, so when mTORC1 is inactivated by nutrient depletion, low concentration of insulin, deprivation of amino acids, or the addition of its antagonist rapamycin, the ULK1 kinase and Atg13 are then activated, forming the ULK1 kinase complex (Table 2), which signals the induction of the AP formation. There is another inductor of autophagy, the AMP activated protein kinase (AMPK), that senses low intracellular energy status and directly activates by phosphorylation to ULK1, and by inhibiting mTORC1 via phosphorylation of Raptor (a subunit of mTORC1) [66–69]. ULK1 phosphorylates Beclin1 at serine 14, which is a component of the PtdIns 3- kinase complex (Table 2) and enhances Vps34 activity — this step is crucial in the AP formation because Vps34 inhibition by 3-methyladenine (3-MA) or wortmannin disrupts the biogenesis. Vps34 synthesizes PIP3 at the sites where AP are assembled; it has been suggested that PIP3 recruits additional factors for AP formation, but its role remains unclear. Beclin1 binding proteins that activate or inhibit AP biogenesis have been identified: the UV radiation resistance-associated gene protein (UVRAG) and Bcl-2 or Bcl-XL, respectively. Beclin-UVRAG interacts with the class C Vps complex proteins, which are part of the endosomal fusion machinery, so this interaction induces AP fusion with lysosomes [50, 53, 70–71].
The next step in AP building is the elongation of the phagophore, which requires membrane input from organelles (such as ER, mitochondria, cytoplasmic membrane, or possibly from
Finally, Atg12-Atg5 conjugates with Atg16L1 forming a tetramer; this tetramer is essential for the elongation but when AP has been completed it dissociates [76–78]. The second ubiquitin-like complex is the microtubule-associated protein 1 light chain 3 (LC3) conjugation system (Table 2). LC3 is a precursor of LC3-I, it is obtained by the cleavage of the protease Atg4B to its carboxyl terminus. LC3-I is attached to phosphatidylethanolamine (PE) by the enzymes E1 and E2- ubiquitin-like Atg7 and Atg3, respectively, obtaining the LC3-II product which forms part of the AP. Notice that the LC3 complex lacks an E3 ubiquitin ligase-like enzyme that could facilitate LC3I-PE conjugation; however, a crosstalk between these two ubiquitin-like systems has been demonstrated by the tetramer Atg12-Atg5-Atg16L1 acting as E3-like enzyme. When AP is formed, LC3 can be recycled from the form LC3II; this is achieved through Atg4 which breaks apart LC3I from PE, and LC3-I and LC3-II assays are widely used for monitoring autophagy [60, 77]. Finally AP moves bidirectionally along microtubules towards the microtubule organizing centre (MTOC) where lysosomes are enriched, then AP fuses with lysosomes forming autolysosomes where the content is degraded and the components are recycled . Atg2 is required for the AP location and can possess a different role when binding to Atg18 in order to target the complex to autophagic membranes . In
|Kinase ser/thr induces autophagy and PA assembly [72, 73–75]|
|Regulator and binding protein of ULK1 complex [72, 73–75]|
R. norvergicus: 89%
|Binding protein and regulator of ULK1, induces PA biogenesis [72, 73–75]|
|Binds to Atg13 in the ULK-Atg13-FIP200 complex, which is important for the stability and basal phosphorylation of Atg13 and ULK1 [72, 73–75]|
|Regulatory kinase subunit of the PtdIns 3- kinase complex [72, 73-75]|
|Necessary for the function of the PtdIn2-kinase complex [72, 73–75]|
|PtdIns 3- kinase produces PI3P and allows the recruitment of PI3P binding proteins like WIPI1/2 and the two conjugation systems [72, 73–75]|
|Modulates AP biogenesis by binding to Vps34 [72, 73–75]|
|Binds Beclin1 enhancing AP biogenesis [72, 73–75]|
|Ubiquitin-like protein covalently joined to Atg5 [72, 73–75]|
|Ubiquitin-like protein covalently attached to Atg12 and interacts with Atg16 [72, 73–75]|
|E1-like enzyme for Atg12-Atg5 and LC3-PE formation [72, 73–75]|
|E2-like enzyme required for Atg12-Atg5 complex|
|Necessary for the assembly of the tetramer Atg12-Atg5-Atg16 [72, 73–75]|
|Conjugated with PE forms part of the AP membrane [72, 73–75] [22, 23–25]|
|E2-like enzyme [72, 73–75] [22, 23–25]|
|Induces LC3-II then helps to recycle LC3 [72, 73–75]|
|E1- like enzyme [72, 73–75]|
|Required for AP localization [72, 73–75]|
|Required for AP localization [72, 73–75]|
|Transmembrane protein that might carry membrane expansion of phagophore [72, 73–75]|
Finally, Atg12-Atg5 conjugates with Atg16L1 forming a tetramer; this tetramer is essential for the elongation but when AP has been completed it dissociates [76–78]. The second ubiquitin-like complex is the microtubule-associated protein 1 light chain 3 (LC3) conjugation system (Table 2). LC3 is a precursor of LC3-I, it is obtained by the cleavage of the protease Atg4B to its carboxyl terminus. LC3-I is attached to phosphatidylethanolamine (PE) by the enzymes E1 and E2- ubiquitin-like Atg7 and Atg3, respectively, obtaining the LC3-II product which forms part of the AP. Notice that the LC3 complex lacks an E3 ubiquitin ligase-like enzyme that could facilitate LC3I-PE conjugation; however, a crosstalk between these two ubiquitin-like systems has been demonstrated by the tetramer Atg12-Atg5-Atg16L1 acting as E3-like enzyme. When AP is formed, LC3 can be recycled from the form LC3II; this is achieved through Atg4 which breaks apart LC3I from PE, and LC3-I and LC3-II assays are widely used for monitoring autophagy [60, 77].
AP moves bidirectionally along microtubules towards the microtubule organizing centre (MTOC) where lysosomes are enriched, then AP fuses with lysosomes forming autolysosomes where the content is degraded and the components are recycled . Atg2 is required for the AP location and can possess a different role when binding to Atg18 in order to target the complex to autophagic membranes . In
The maintenance of homeostasis in pluricellular and unicellular organisms is achieved through lots of mechanisms, one of the most important of which is related to the death of the cell itself. In this way, cell death regulates the number of cells in a tissue or a colony, and the removal of damaged cells. In 1963, Lockshin introduced the term Programmed Cell Death (PCD) in order to define the programmed and controlled self-destruction process in a local and temporal way [83–84]. There are many ways for a cell to die; one of them is via apoptosis. The term apoptosis was introduced by Kerr and colleagues in 1972, which is defined as a highly coordinated cellular suicide programme controlled principally by zymogens (i.e., caspases and metacaspases), proteins of the Bcl-2 family, and mitochondria . The Nomenclature Committee on Cell Death established the morphological and biochemical changes in the apoptotic cell, such as membrane blebbing, cell shrinkage (pyknosis), chromatin condensation plus fragmentation (karyorrhexis), formation of membrane bound cell fragments (apoptotic bodies), decrease in mitochondrial inner transmembrane potential, selective cleavage of various cellular proteins, and the translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane .
The importance of Bcl-2 proteins relies on Cyt C, which in basal conditions works at the respiratory chain but plays a different role in the cytoplasmic space: Cyt C oligomerizes with the adaptor protein Apoptosis protease activating factor-1 (Apaf-1), forming the complex known as apoptosome [98, 99]. The apoptosome activates by proteolytic cleavage to caspase-9 which is one of the cascade cysteine-aspartate proteases (caspases); in other words, caspases are liberated from their inhibitory prodomain [98, 99]. Once caspase-9 is activated, the downstream zymogens procaspase 3/7 are activated as caspase 3/7, then they attach to specific substrates in the cell leading to cell dismantling but they must first be released from their endogenous inhibitor X-linked inhibitor of apoptosis (XIAP). XIAP activity is inhibited by SMAC/ DIABLO and HtrA2/Omi, which should be remembered as mitochondrial proteins that were released along Cyt C [94, 95, 100]. In
On the other hand, the extrinsic pathway start when death ligands such as tumour necrosis factor (TNF), Fas ligand (FasL), TNF-related apoptosis-inducing ligand (TRAIL), among others, join and activate their respective transmembrane death receptor, such as Fas. The interaction of death ligands with death receptors result in the recruitment of adaptor proteins like the Fas-associated death domain protein (FADD), which recruits, aggregates, and promotes procaspase-8 activation. Caspase-8 switch on procaspase 3/7 and the Bid protein through is proteolysis. At this point, a crosstalk between the extrinsic and intrinsic pathways are mediated by Bid activation since truncated Bid (tBid) promotes Cyt-C by interacting with Bax, leading to Bax insertion in the mitochondrial membrane as an oligomer pore [93–95].
Study of apoptosis is difficult in higher eukaryotes due to the complexity of the phenomena itself, which is why it was thought until recently that unicellular organisms could not have PCD machinery because it would mean that the organism could orchestrate its suicide, so yeast were employed as purely naïve backgrounds for studying proteins’ interaction. In 1997, B. Ink and JM. Jurgensmeier independently performed a yeast two-hybrid system in
Caspases are the main components of the apoptotic pathway, and are not found in
Sz. pombe: Heterologous expression systems of proteins
Fission yeast is a useful system for studying the function and regulation of genes, and an excellent host for heterologous expression of molecules derived particularly from higher eukaryotes because it produces high cell densities, short fermentation times, and the use of chemically defined media . Difficulties in the production and purification of heterologous proteins are related mainly to proteolytic degradation of gene products by specific proteases of the host . This makes it highly important to obtain strains that have specific mutations eliminating the activity of proteases. Success of this expression is based on the use of genome-reduced strains with the deletion of unnecessary genes. Gene-deletion technology used for this purpose is the LATOUR (latency to universal rescue) method, which eliminates a DNA segment of more than 100 kb [119, 120]. This strategy of gene deletion is useful for identifying genes that are essential to the yeast . The
This chapter discussed some topics related to the employment of
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