Phosphoinositide‐binding proteins in autophagy

Abstract

Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes

“…This provides for their specific molecular interactions with target proteins. Such proteins thus contain binding sites that are specific for certain PI metabolites, e.g., the Pleckstrin homology (PH) domains, with a distinct affinity of interaction [ 38 , 47 , 48 ]. In addition, the phosphoinositides have a diacylglycerol and a lipid constituent with hydrophobic properties that enable interaction with membranes or other hydrophobic domains, whereas the IP is soluble in aqueous environments.…”

Synthesis and Cellular Labeling of Caged Phosphatidylinositol Derivatives

“…Phosphoinositides (PIPx) are quite rare lipids that serve as membrane-bound anchors for a variety of proteins carrying specific lipid-recognizing domains, such as PH domains for PIP 2 and PIP 3 isoforms, PX domains for PI(4)P and FYVE domains for PI(3)P. [3] Their biosynthesis is spread out over various cellular membrane systems and in all cases starts from phosphatidylinositol (PI). Most phosphoinositides are well studied but the functions of PI beyond serving as the biosynthetic precursor for other phosphoinositides are elusive.…”

Local detection of PtdIns3P at autophagosome biogenesis membrane platforms

“…[1][2][3] Phosphatidylinositol 3-phosphate (PtdIns3P) is critical to early endosome function, 4 , 5 and a role of PtdIns3P in autophagy has been documented recently. 6,7 In both the endocytic and autophagic pathways PtdIns3P recruits proteins bearing FYVE, PX (PhoX homology), or PROPPIN (b-propellers that bind polyphosphoinositides) domains. [7][8][9] An example of PtdIns3P function at endosomes is illustrated by the FYVE-domain-containing EEA1 (early endosome antigen 1) protein, which is essential for early endosome homotypic fusion.…”

“…6,7 In both the endocytic and autophagic pathways PtdIns3P recruits proteins bearing FYVE, PX (PhoX homology), or PROPPIN (b-propellers that bind polyphosphoinositides) domains. [7][8][9] An example of PtdIns3P function at endosomes is illustrated by the FYVE-domain-containing EEA1 (early endosome antigen 1) protein, which is essential for early endosome homotypic fusion. 10 PtdIns3P is also required for intralumenal vesicle biogenesis in early endosomes; 11,12 for this function, PtdIns3P recruits ESCRT complex proteins such as HGS/Hrs and TSG101.…”