Autophagy in unicellular eukaryotes

Abstract

Cells need a constant supply of precursors to enable the production of macromolecules to sustain growth and survival. Unlike metazoans, unicellular eukaryotes depend exclusively on the extracellular medium for this supply. When environmental nutrients become depleted, existing cytoplasmic components will be catabolized by (macro)autophagy in order to re-use building blocks and to support ATP production. In many cases, autophagy takes care of cellular housekeeping to sustain cellular viability. Autophagy encompasses a multitude of related and often highly specific processes that are implicated in both biogenetic and catabolic processes. Recent data indicate that in some unicellular eukaryotes that undergo profound differentiation during their life cycle (e.g. kinetoplastid parasites and amoebes), autophagy is essential for the developmental change that allows the cell to adapt to a new host or form spores. This review summarizes the knowledge on the molecular mechanisms of autophagy as well as the cytoplasm-to-vacuole-targeting pathway, pexophagy, mitophagy, ER-phagy, ribophagy and piecemeal microautophagy of the nucleus, all highly selective forms of autophagy that have first been uncovered in yeast species. Additionally, a detailed analysis will be presented on the state of knowledge on autophagy in non-yeast unicellular eukaryotes with emphasis on the role of this process in differentiation.

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…Ubiquitin-like ligases Atg7/Atg10 activate the conjugation of Atg12 onto Atg5, which complex in pairs with Atg16L. The latter complex elicits curvature into the growing phagophore membrane through recruitment of Atg4 -cleaved LC3B-II/Atg8, which is conjugated to phosphatidylethanolamine (PE) for initiating the formation and maturation of autophagic vesicles following its activation by Atg7/ Atg3 (Figure 8) [86] for more detailed discussion of the molecular mechanisms of autophagy in unicellular eukaryotes). The bioinformatic evidence disclosed the existence of putative homologs of ATG genes, including TgATG1, TgATG3, TgATG7, TgATG8, TgATG18, TgATG20, and TgVPS34 and the absence of TgATG5 and TgATG12 [87,88], which supports the notion of the evolutionarily conservation of autophagy.…”

Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum

“…' In the past two decades, the growth in our understanding of microautophagic processes has come about almost entirely from studies carried out in baker's yeast, Saccharomyces cerevisiae, and the methylotrophic yeasts, Pichia pastoris and Hansenula polymorpha. [8][9][10][11][12][13][14][15][16][17] These studies have shed some light on longstanding questions concerning microautophagy, including the mechanism of membrane vacuolar/lysosomal invagination and the protein components (or other factors, possibly lipids) that are involved in formation and eventual scission of the microautophagic vesicle. By contrast, few investigators have studied microautophagy in mammalian cells as a primary focus, and consequently our understanding has remained limited.…”

Receptor protein complexes are in control of autophagy

“…In order to be ultimately degraded, cargo with ligand must go through a cascade of sequentially regulated steps involving a cohort of molecular players (e.g., receptors and Atg proteins) and intricate membrane dynamic events (e.g., autophagosome formation, and their subsequent fusion with the vacuole/lysosome membrane). 1,4,5,7,8,[10][11][12] The specific ligands responsible for targeting various cargos for degradation by autophagy are just beginning to be revealed, but ligands for some autophagy cargos have been identified. Examples include mitochondria [addition of ubiquitin (Ub) to one or more outer membrane proteins, including VDAC1, MFN1/2 and BNIP1, by the E3 Ub ligase PARK2/PARKIN in mammals], [13][14][15] peroxisomes (Pex3 and Pex14 in yeasts) [16][17][18] or protein aggregates (Ub, mutant SOD1 or STAT5A_ΔE18 in mammals) 9,10,[19][20][21][22] ( Table 1).…”

“…The cargos include nonspecific cytoplasmic substrates, as well as vacuolar hydrolase precursors, protein aggregates, unwanted or damaged organelles and invasive microorganisms. [1][2][3][4][5][6][7] The signature of such a sophisticated and tightly regulated autophagic degradation pathway, is that, in selective mode, almost all (if not all) autophagic cargos destined for degradation will be processed by a receptor protein complex. [8][9][10][11] Therein lies a conundrum: How is a given autophagic cargo selected from many others, and what † These authors contributed equally to this work.…”

“…Specifically, CALCOCO2 and OPTN bind to the certain types of autophagic cargo, such as the endoplasmic reticulum or lipid droplets, have not yet been identified. 4 In general, components of the autophagic cargo may be either recognized directly by a receptor, or first modified with Ub by an E3 Ub ligase and then recognized by a Ub-binding receptor. Ubiquitination of cargo proteins often triggers selective autophagy in mammalian cells.…”