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. 2022 Apr 30;106(9-10):3369–3395. doi: 10.1007/s00253-022-11934-x

Table 1.

Summary of the main physiological and molecular phenomena awaken by specific stress factors in Y. lipolytica cells

Stress factor Cellular response References
Low-oxygen availability
Different pO2 levels Glucose concentration-dependent filamentation mediated via RAS-cAMP-PKA; in the presence of cAMP – no filamentation (Ruiz-Herrera and Sentandreu 2002; Bellou et al. 2014; Timoumi et al. 2017a, 2018; Gorczyca et al. 2020; Lesage et al. 2021)
Downregulation of lipid biosynthesis
Restorable growth rate limitation
Acidity – pH
pH 3.0 Higher energy requirement (Madshus 1988; Cogo et al. 2020)
Increased abundance and activity of plasma membrane H + -ATPase Pma1p
pH 4.0/3.0 Intracellular proton extrusion across the mitochondrial inner membrane – the major mechanism contributing to the pH homeostasis (Guo et al. 2016)
Increased energy demand – upregulation of glycolysis -– Pgk1p, Gut2p, Eno2p, Tpi1p, Tdh3p, Fba1p, Pck1p

Key role of mitochondria (and increased energy demand):

Upregulation of mitochondrial proteins – Por1p, Cit1p, Pda1p, Pdb1p, Mdh1p, Icl1p, Kgd2p, Acs2p

Upregulation in mitochondrial electron transport chain and ATP synthesis – Nuamp, Nuemp, Nufmp, Qcr2p, Atp1-2–3-7p, Cdc48p, Afg1p

Onset of oxidative stress response:

Increased synthesis of amino acids– Aat2p, Leu1p, Gcv2p, Sam2p, Met6p, Ilv5p, Ses1p, Gat1p, Shm1p

Upregulation of molecular chaperones (Kar2p, Sse1p, Ssa4p)

Upregulation of Sod2p

Enhanced synthesis of aKGA
pH 9.0 Drop in intracellular sugar amounts by 25% (Sekova et al. 2019)
Changes in intracellular sugar composition – increase in MAN, no glucose, no TRE
Drop in storage lipids – lipid bodies and/or membrane lipids by ~ 30% and 36%
Increased level of saturated fatty acids (sFAs) in mitochondria
Upregulation of Sod2p activity
Reduced glutathione (GSH) concentration
pH 9.0 Increased chaperoning capacity – rotamase, Hsps (Sekova et al. 2021)

Substantial changes in mitochondria activity – upregulation of malate dehydrogenase, VDAC porin, NADPH dehydrogenase, mitochondrial chaperones, and pore constituents

Mitochondrial VDAC was deemed as one of the key proteins responding to the alkaline pH

Enhanced energy demand – upregulation of TPI1/Tpi1p and GAPDH
pH 4.5/pH 7.0 Glucose concentration-dependent filamentation mediated via RAS-cAMP-PKA; in the presence of cAMP – no filamentation (Timoumi et al. 2017b; Lesage et al. 2021)
Temperature
38 ℃ twofold increase in the total cytosolic sugar content with concurrent substitution of MAN for TRE; 10 × increased concentration of arabitol (Sekova et al. 2019)
Drop in the storage and membrane lipid levels (by 35%), changes in their composition (like > threefold decrease in the sterols content and appearance of some sterol esters)
Increased activities of Sod2p and catalase Ctt1p
threefold increase in GSH level, tenfold increase in glutathione disulfide (GSSG) pool
Lipid bodies-nucleus-mitochondria continua – active migration of lipids
37 ℃ Enlargement of mitochondria, enhanced number and enlargement of peroxisomes, formation of lipid and polyphosphate granules, formation of globular surface structures, enriched in silicone (Biryukova et al. 2011; Arinbasarova et al. 2018)
Dimorphic transition – unipolar growth, asymmetric division, large, polarly located vacuoles, and repression of cell separation after division
37 ℃ Filamentation – elongation factor increased by 25% (Kawasse et al. 2003)
42 ℃ Increased concentration of MAN (fourfold) and aKGA (threefold) (Kubiak et al. 2021)
38 ℃ Induction of heat-shock proteins synthesis (Sekova et al. 2021)
Cell shrinkage – cofilin (F20856p)
Upregulation in thioredoxin (Trx1p), formate dehydrogenase (Fdh1p)
Upregulation of fructose-bisphosphate aldolase (Fba1p) enhanced TRE synthesis
Thermotolerant strain BBE-18 Upregulation of amino acids synthesis, including Ala, Arg, Asn, Gln, and Met (Qiu et al. 2021)
Upregulation of phosphoglucomutase PGM1, pyruvate kinase PYK1, and erythrose reductase ER3
Key role of thiamine synthesis (E32681g, E35222g, A12573g, and F26521g) evidenced
Dehydration
Drying or freezing Injury of the plasma membrane, changes in its fluidity and organization, lipids peroxidation, nucleic acids degradation, proteins dehydration and aggregation, cell wall disruption, causing cell shape alteration, and loss of cell integrity (Pénicaud et al. 2014)
Oxidative agents
0.5 mM H2O2 Accumulation of polyphosphate granules (Biryukova et al. 2011)
0.5 mM H2O2 Globular structures on the cell wall surface – surface globules contain silicone (Arinbasarova et al. 2018)
Formation of the multi-layered plasma membrane and multiple membrane vesicles localized in proximity to the cell wall
Abrupt increase in cAMP and the following drop – activation of stress defense mechanisms

1 mM paraquat hyperbaric air (3 or 5 bar)

50 mM H2O2

Lipid peroxidation (Lopes et al. 2013)
Increased GSH content
Upregulation of Glr1p and Sod2p activity
H2O2 – Ctt1p activity induction
20 mM H2O2 Induced filamentation (Kawasse et al. 2003)
Acetate Decreased lipogenic potential (Xu et al. 2017)
Toxic metals and chemicals
Heavy metal ions Filamentation (Bankar et al. 2018)
Formation of nanostructures on the yeast cell surfaces
Faulty cytokinesis
Fe2+ and pH 3.0 Decreased abundance and activity of plasma membrane H + -ATPase Pma1p (Cogo et al. 2020)
50 µM uranium Increased cell size, irregular cell surfaces, membrane permeabilization (Kolhe et al. 2020)
Enhanced ROS generation, lipid peroxidation, transient RNA degradation, and protein oxidation
Upregulation of Sod2p activity, but not Ctt1p
Disappearance of vacuoles and other intracellular organelles
50 µM uranium Upregulation of transmembrane transporters (MFS and ATPase-coupled transmembrane transporter) (Kolhe et al. 2021)
Oxidative stress response – upregulation of GSH transferase/peroxidase, peptide-methionine (R)-S-oxide reductase and other oxidoreductases
DNA damage repair – mismatch repair, chromatin condensation (RCC1)
Structural rearrangements in cell wall – 1,3-β-glucanosyltransferase, chitin synthase
Cell division arrest at G2 phase – SMC2, SMC4, YCS4, YCG1, HOF1
Ionic liquid Damage of cell envelope – cavities, dents, and wrinkles (Walker et al. 2019)
Onset of restructuring within the cell wall and plasma membrane
Sterol biosynthesis was the only “lipid pathway” significantly perturbed
twofold increase in ergosterol content
Osmo-active compounds
Different effectors

Induction of HOG pathway:

Sln1-Ypd1-Ssk1/2 – cytoplasmic functions of Hog1p:

stabilization of stress-response transcripts

Ubp3-driven turnover of specific transcription factors and/or RNA Pol II

Sln1-Ypd1-Skn7 – nuclear functions of Hog1p:

direct interaction with transcription factors and chromatin remodeling factors

transcription of stress-response genes

A rapid and transient delay at various stages of the cell cycle
Depending on the osmo-active compound – induction or repression of rs-Prot synthesis
0.5–1.0 M glycerol/glucose Induction of ERY-dependent but HOG-independent osmoprotection mechanism (Rzechonek et al. 2020)
6–9% NaCl Decrease in cell size – rapid concentration of intracellular solutes, e.g., amino acids like proline, alanine (Andreishcheva et al. 1999)
Rapid action of cell membrane pumps and cytoskeleton
3% NaCl = 4.21 Osm kg−1 Promoted synthesis of ERY – upregulation AKRs: Gcy12p, Tkl1p and Gcy15p (Yang et al. 2015)
Increased demand for energy – upregulation of a panel of proteins involved in glycolysis (Tpi1p), TCA (AcnAp; Mdh2p), and respiration (Cox4p, Mcr1p)
Onset of oxidative stress response – upregulation of Ctt1p, Sod2p Ahp1p, Sti1p, Hsp20p, Hsp12p
Upregulation of amino acids synthesis – Met6p, Shmtp
Downregulation of Gdh1p to decrease amino acids efflux to TCA
Adjustment of ions equilibrium – downregulation of membrane K + channel
Downregulation of protein synthesis (Tef1p, ribosomal 60S proteins L2 and L4, seryl-tRNA synthetase)
Upregulation of Prb1p vacuolar protease
360 g L−1 sorbitol = 3 Osm kg−1 Upregulation of AKRs involved in polyols synthesis – 7 × higher concentration of MAN, 2 × ERY – Gcy13p, Gcy12p, A19910p, F24937p, D08778p (Kubiak-Szymendera et al. 2021a, b)
Downregulation of TCA and FA synthesis – threefold reduction in CA concentration
High increase in chaperoning and folding capacity – HSP20, STI1, FMO1, SSA6/7, and Ssa6p, Ssa8p, Hsp104p, Hsp90p, ER-localized E25696p, F00880p, and mitochondrial Hsp78p, Isu1p
No evidence for HOG1 upregulation at gene expression/protein abundance level, but upregulation of SKN7 and SKO1
Enhanced TRE synthesis – TPS1, TPS2, TPS3
Onset of oxidative stress response
Enhanced demand for energy – upregulation of D08602p, F24409p, D09933p, and transcriptional activation of TPI1
Sequestration of membrane channels and transporters – upregulation of cellular membrane invagination and endocytosis factors (Pil1p/Lsp1p), vesicle transportation (B14102p, F27379p), and the major vacuolar protease Prb1p
Downregulation of protein synthesis-related processes – Tef1p, ribosomal 60S proteins L2 and L4, and eight amino acid-tRNA synthetases, ribosome biogenesis (E31625p, F12661p) and biosynthesis of amino acids (Aro10p, Bat2p, Pro3p, CysK-Met25p, MetBp) increased amounts of uncharged tRNAs
Over-synthesis of rs-Prots – strongly dependent on biochemical properties of the rs-Prots
Over-synthesis of burdensome r(s)-Prots Significant increase in the synthesis of stress-response molecule – MAN (Korpys-Woźniak et al. 2020)
Over-synthesis of two demanding rs-Prots Significantly increased demand for the substrate even at the reduced growth rate (Gorczyca et al. 2022)
Over-synthesis of burdensome r(s)-Prots Upregulated biological process – ion homeostasis (Korpys-Woźniak and Celińska 2021)
Increased abundance of vacuolar sorting and vacuolar proteases
Downregulation of ribosome biogenesis and rRNA processing
Over-synthesis of highly synthesized and highly secreted rs-Prots Increased energy demand – enhanced expression of genes localized to mitochondria
Significant upregulation of oxidative stress response genes
Downregulation of protein degradation, autophagy, and vacuolar protein sorting factors
Growth arrest phase (G1 phase)
Released ribosome assembly from inhibition
Over-synthesis of two rs-Prots – larger and smaller Accumulation of the larger protein’s transcript – indicating insufficient translation capacity (Swietalski et al. 2020)
Limitation of the smaller protein secretion level
Over-synthesis of two complex rs-Prots Accumulation of saturated FAs—marker of ER-stress (Wei et al. 2019, 2021)
Competition among synthesis/secretion of the protein and lipid synthesis