InteractiveFly: GeneBrief

fab1: Biological Overview | References

Gene name - fab1

Synonyms - CG6355

Cytological map position - 54E9-54E9

Function - signaling

Keywords - Vesicles, autophagy

Symbol - fab1

FlyBase ID: FBgn0028741

Genetic map position - 2R: 13,661,469..13,669,417 [-]

Classification - FYVE domain, Phosphatidylinositol phosphate kinase

Cellular location - cytoplasmic

NCBI link: EntrezGene

fab1 orthologs: Biolitmine

The trafficking of endocytosed receptors through phosphatidylinositol 3-phosphate [PtdIns(3)P]-containing endosomes is thought to attenuate their signaling. This study shows that the PtdIns(3)P 5-kinase Fab1/PIKfyve controls trafficking but not silencing of endocytosed receptors. Drosophila fab1 mutants contain undetectable phosphatidylinositol 3,5-bisphosphate levels, show profound increases in cell and organ size, and die at the pupal stage. Mutant larvae contain highly enlarged multivesicular bodies and late endosomes that are inefficiently acidified. Clones of fab1 mutant cells accumulate Wingless and Notch, similarly to cells lacking Hrs, Vps25, and Tsg101, components of the endosomal sorting machinery for ubiquitinated membrane proteins. However, whereas hrs, vps25, and tsg101 mutant cell clones accumulate ubiquitinated cargo, this is not the case with fab1 mutants. Even though endocytic receptor trafficking is impaired in fab1 mutants, Notch, Wingless, and Dpp signaling is unaffected. It is concluded that Fab1, despite its importance for endosomal functions, is not required for receptor silencing. This is consistent with the possibility that Fab1 functions at a late stage in endocytic receptor trafficking, at a point when signal termination has occurred (Rusten, 2006).

Cell growth, survival, proliferation, and differentiation are controlled by signals that activate their cognate receptors on the cell surface. Important examples include the soluble ligand Wnt (and its Drosophila homologue Wingless) and the membrane bound ligand Delta, which bind to G protein-coupled receptors and Notch receptors, respectively, on receiving cells. During development and normal physiology, the levels of the ligands and their receptors are tightly controlled in time and space (Rusten, 2006).

Receptor density at the cell surface is an important determinant of signaling responses, and there are both slow and fast mechanisms attenuating receptor levels. Transcriptional down-regulation is a slow and long-lasting mechanism, whereas posttranslational modification and/or internalization represent fast ways to reduce the amounts of functional receptors on the cell surface. Internalization of many receptors, including Notch and Wnt receptors, is followed by their transport from endosomes to lysosomes, where they become degraded, resulting in a transient reduction in the ability of cells to receive signals. Adding to the complexity of signaling regulation is the fact that ligand-bound receptors may also signal from endosomal membranes, and their signaling output from endosomes may differ from the output triggered from the plasma membrane (Rusten, 2006).

The key roles of the endocytic pathway in cell signaling are highlighted by the analyses of mutants interfering with endocytic trafficking. Such an example is provided by Hrs, a protein that sorts ubiquitinated receptors into intraluminal vesicles of multivesicular bodies (MVBs), destined for degradation in lysosomes. Drosophila hrs mutants show impaired sorting of receptors into MVBs, causing their accumulation in early endosomes. In hrs mutants, Dpp (a transforming growth factor-β homologue) and epidermal growth factor receptor signaling is enhanced, presumably because the activated receptors have a prolonged residence time in the limiting membrane of endosomes. Likewise, mutations of two subunits of the endosomal sorting complex required for transport (ESCRT)-I and -II, Tsg101 and Vps25, which are thought to function immediately downstream of Hrs, cause endosomal accumulation of receptors and tumor-like overproliferation in a cell nonautonomous manner due to increased Notch signaling. This supports the view that proper endocytic traffic has an important antitumorigenic function (Rusten, 2006).

Hrs is recruited to endosome membranes by binding the phosphoinositide (PI) phosphatidylinositol (PtdIns) 3-phosphate [PtdIns(3)P], formed by phosphorylation of PtdIns by a class III PI 3-kinase. PtdIns(3)P is specifically localized to endosomal membranes and not only recruits Hrs but also several other proteins containing FYVE or PX domains (Ellson, 2002; Stenmark, 2002). Class III PI 3-kinase and PtdIns(3)P are thus crucial regulators of endocytic trafficking, mediating endosome fusion as well as degradative sorting, recycling, and retrograde trafficking to the biosynthetic pathway (Lindmo, 2006a). PtdIns(3)P is metabolized by dephosphorylation and by lysosomal lipases. In addition, this PI can be phosphorylated in the 5-position of the inositol headgroup, giving rise to phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2]. The kinase catalyzing this phosphorylation, Fab1, was first characterized in yeast. Saccharomyces cerevisiae fab1 mutants have abnormally enlarged vacuoles and show impaired trafficking of the ubiquinated cargo carboxypeptidase S to the vacuole lumen (Odorizzi, 1998). Fab1 is evolutionarily conserved, and overexpression of a kinase-dead mutant of the mammalian Fab1 homologue PIKfyve in cultured cells has been reported to inhibit fluid-phase transport of endocytic markers but not recycling/degradation of endocytosed receptors or sorting of procathepsin D (Ikonomov, 2001; Ikonomov, 2003). Moreover, PIKfyve has been found to be phosphorylated by the PI 3-kinase–regulated protein kinase, PKB, after insulin stimulation (Berwick, 2004), and PIKfyve colocalizes with a highly motile subpopulation of vesicles containing insulin-responsive aminopeptidase (Rusten, 2006).

These findings indicate that Fab1/PIKfyve plays a role in controlling specific membrane trafficking processes, but its functions in signal termination and in the physiology of a multicellular organism are not known. To address this, Drosophila fab1 mutants were generated and their phenotype was studied with respect to survival, growth, membrane trafficking and cell signaling. It was found that the activity of Drosophila Fab1 is essential for development and cell volume control and that its inactivation leads to endosomal accumulation of Wingless and Notch. Remarkably, this accumulation is not accompanied by increased signaling, indicating that Fab1, unlike Hrs and ESCRT-I and -II, is not involved in receptor silencing (Rusten, 2006).

That endosomal sorting of ubiquitinated cargoes is of great physiological importance is illustrated by studies of Drosophila mutants of the two ESCRT subunits, Tsg101 and Vps25. Loss of these proteins yields endosomal accumulation of receptors and ubiquitin, similarly to hrs mutants. Importantly, loss of Tsg101 and Vps25 in clones of cells causes a tumor-like overproliferation of adjacent tissue due to increased Notch-mediated signaling. No such effects were observed with fab1 mutant clones consistent with the finding that Notch signaling (as well as Wg and Dpp signaling) is unaffected in fab1 mutants. Thus, Fab1, unlike Hrs and ESCRT-I and -II proteins, does not seem to play any role in receptor silencing, even though it is important for receptor degradation. This is reminiscent of the ESCRT-III subunit hVps24, which mediates degradation but not silencing of the epidermal growth factor receptor. Moreover, it is interesting to note that impaired Hrs, Tsg101, or Vps25 function causes a strong accumulation of ubiquitinated proteins in endosomes, whereas this was not observed in fab1 mutant clones. These results, together with the fact that Fab1 mainly localizes to later endocytic structures than Hrs, suggest that Fab1 functions later than Hrs and ESCRT-I/-II in endocytic trafficking, at a point beyond receptor deubiquitination and signal termination (Rusten, 2006).

Studies in yeast and mammalian cells have suggested a role for Fab1 in endocytic membrane homeostasis, although its exact functions are not known. Indeed, confocal and EM revealed the accumulation of larger late endosomes in fab1 mutant Drosophila cells, consistent with previous studies in fab1 yeast and overexpression of kinase-dead PIKfyve in mammalian cells. The findings that the enlarged vacuoles in fab1 yeast mutants and late endosomes in kinase-dead PIKfyve-overexpressing cells contain few internal vesicles have suggested the possibility that Fab1 could mediate formation of such vesicles (Odorizzi, 1998; Ikonomov, 2001). In agreement with this, in fab1 mutant Drosophila cells enlarged endosomes were frequently observed with few or no intraluminal vesicles. However, in the fab1 mutants highly enlarged MVBs were frequently observed that were filled with numerous normal-sized intraluminal vesicles. This indicates that the increased endosome size in the absence of Fab1 cannot be explained by an inhibited formation of intraluminal vesicles, in contrast to what has been reported for Hrs. A more likely explanation is that late endosomes expand in fab1 mutants because of inhibited retrograde membrane flux to the biosynthetic and early endocytic pathways (Rusten, 2006).

Cell and organ size is controlled by genetic, hormonal, and environmental inputs. In particular, insulin signaling is important for growth, and the functions of the downstream class I PI 3-kinases in growth signaling are well characterized. The striking growth phenotypes observed in fab1 mutants indicate that PtdIns(3)P 5-kinase also regulates cell size. Interestingly, however, whereas PI 3-kinases promote growth, the current findings indicate that Fab1 has an inhibitory effect on cell size. Garland cells were strongly enlarged in fab1 mutants, suggesting a function of Fab1 in negative cell size regulation. In addition, fab1 deficiency led to a thickening of legs and enlargement of wings and heads, demonstrating a role for Fab1 in attenuating organ size. Overexpression of Drosophila Fab1 did not cause any overt growth-inhibitory effects, consistent with the finding that overexpression of Fab1 in yeast does not yield any increase in PtdIns(3,5)P2 levels, presumably because regulatory components are limiting. No strong genetic interactions were detected between fab1 and mutants in components of the insulin signaling pathway, suggesting that the increased cell size in fab1 mutants may not be due to up-regulation of this pathway. Instead, there was a striking correlation between cell size and endosome overgrowth in fab1 mutant larvae. Thus, the increased cell and organ size in fab1 mutants may be due to the volume expansion of endosomes. It is therefore proposed that Fab1, through its effects on endosome morphology, functions in negative regulation of cell volume. Further work will reveal whether Fab1 also regulates cell size by additional mechanisms (Rusten, 2006).

ESCRTs and Fab1 regulate distinct steps of autophagy

Eukaryotes use autophagy to turn over organelles, protein aggregates, and cytoplasmic constituents (for a review see Lee, 2009 Autophagy in neurodegeneration: two sides of the same coin). The impairment of autophagy causes developmental defects, starvation sensitivity, the accumulation of protein aggregates, neuronal degradation, and cell death. Double-membraned autophagosomes sequester cytoplasm and fuse with endosomes or lysosomes in higher eukaryotes, but the importance of the endocytic pathway for autophagy and associated disease is not known. This study shows that regulators of endosomal biogenesis and functions play a critical role in autophagy in Drosophila. Genetic and ultrastructural analysis showed that subunits of endosomal sorting complex required for transport (ESCRT)-I, -II and -III, as well as their regulatory ATPase Vps4 and the endosomal PtdIns(3)P 5-kinase Fab1, all are required for autophagy. Although the loss of ESCRT or Vps4 function caused the accumulation of autophagosomes, probably because of inhibited fusion with the endolysosomal system, Fab1 activity was necessary for the maturation of autolysosomes. Importantly, reduced ESCRT functions aggravated polyglutamine-induced neurotoxicity in a model for Huntington's disease. Thus, this study links ESCRT function with autophagy and aggregate-induced neurodegeneration, thereby providing a plausible explanation for the fact that ESCRT mutations are involved in inherited neurodegenerative disease in humans (Rusten, 2007).

An increased understanding of the mechanisms that regulate macroautophagy (referred to as autophagy) is critical because the dysregulation of autophagy is seen in many human pathologies, including cancer and neurodegeneration. Insight into the molecular mechanisms of autophagy stems largely from genetic screens in yeast, which have identified two ubiquitin-like conjugation machineries necessary for autophagosome formation. Although the requirement for these machineries has been conserved to higher eukaryotes, the molecular mechanisms of autophagic transport to the lysosomes in metazoans are less clear. In yeast, the autophagosome fuses directly with the vacuole (lysosome) in a step requiring the small GTPase, Ypt7/Rab7, the HOPS-C complex, and SNAREs. In contrast, it is well established that fusion structures between autophagosomes and endosomal compartments, called amphisomes, are formed in higher eukaryotes. This raises the question of whether autophagy in metazoans is controlled by components that regulate endosome biogenesis and sorting functions. Endosomal sorting complexes required for transport (ESCRTs) are interesting in this context because these complexes mediate multivesicular body (MVB) biogenesis and degradative protein sorting and because their dysfunction is associated with neurodegenerative disease in humans. Another candidate regulator of autophagy is the PtdIns(3)P 5-kinase Fab1/PIKfyve, which controls late-endosomal membrane homeostasis, and whose inactivation is associated with an inherited form of fleck corneal dystrophy (Li, 2005; Rusten, 2007 and references therein).

Autophagy in Drosophila is regulated by global nutritional and developmental cues such as amino acid availability and hormonal signaling (Scott, 2004; Rusten, 2004). In order to overcome confounding effects from such systemic influences, trafficking mutants were analyzed in clones of cells by using surrounding wild-type cells as a control. Mutant clones were induced by FLP-FRT technology in animals expressing Gal4. The clones were recognized by the loss of a upstream activating sequence (UAS)-myristylated red fluorescent protein (mRFP) transgene present on the homologous chromosome. In order to follow autophagy, a transgene was used located on another chromosome that carries UAS-GFP-Atg8a (GFP: green fluorescent protein), which labels autophagosomes and autolysosomes (Rusten, 2007).

To address the role of the endosomal sorting machinery in autophagy, flies were selected containing null mutations in members of ESCRT-I (vps28), -II (vps25), and -III (vps32) obtained in a screen for tumor suppressors (Vaccari, 2005; Sevrioukov, 2005). Clones of the ovarian follicular epithelium in stage 8 or 9 egg chambers, in which no autophagy is normally detectable, were investigated. Interestingly, mutant follicular epithelial cells of vps28, vps25, and vps32 all accumulated intracellular structures positive for GFP-Atg8a in a cell-autonomous manner. A similar appearance of GFP-Atg8a structures was observed when cells were made mutant for fab1, involved in late-endocytic trafficking and membrane homeostasis. The accumulation of GFP-Atg8a in ESCRT and fab1 mutant cells under nonstarved conditions suggested that autophagic structures accumulated as a result of steady-state, low-level autophagic sequestration coupled with incomplete digestion in these cells (Rusten, 2007).

Next focus was placed on ESCRT function in the fat body, the Drosophila counterpart of mammalian liver and adipose tissue, where the regulation of autophagy has been extensively studied. In well-fed stage L1, L2, and early L3 wild-type larvae, very little autophagy was observable in the fat body either by electron microscopy or with the GFP-Atg8a reporter. Nevertheless, as shown previously (Scott, 2004; Rusten, 2004), autophagy was rapidly induced in this tissue by amino acid starvation. As in follicular epithelial cells, fat body cells lacking ESCRT components, but not their wild-type neighbors, accumulated GFP-Atg8a in subcellular structures even under nonstarved conditions. The starvation of L2 larvae for 4 hr resulted in the appearance of autophagic structures in both the vps25 mutant cells and surrounding control cells. Together, these results confirm the data from the follicular epithelial clones and also show that the physiological control of starvation-induced autophagy is still intact in animals containing ESCRT mutant cells (Rusten, 2007).

The AAA ATPase Vps4 (Vps: vacuolar protein sorting) interacts with ESCRT-III components and is necessary for ESCRT-III function, apparently through disassembling multimeric ESCRT-III complexes on the endosomal membrane. An ATPase-deficient version of Vps4 acts like a dominant-negative mutant in endosomal sorting and transport. In agreement with earlier findings in mammalian cells, the expression of a hemagglutinin (HA)-tagged Drosophila Vps4DN produced a strong accumulation of GFP-Atg8a in all fat body cells of nonstarved larvae. This indicates that not only ESCRTs but also their disassembling ATPase is required for autophagy (Rusten, 2007).

To investigate the nature of the GFP-Atg8a-containing profiles, wild-type and ESCRT mutant tissues were studied by using established markers of endosomes and lysosomes. In ESCRT mutant cells of Drosophila, monoubiquitinated transmembrane receptors destined for degradation in the lysosome accumulate in an endosomal compartment positive for Hrs, a peripheral membrane marker for the sorting endosome. In marked contrast to transmembrane receptors, GFP-Atg8a-positive structures in ESCRT mutant or Vps4DN-expressing cells did not colocalize with Hrs, whereas such colocalization was evident in wild-type L3 fat body cells. These results indicate that the compartments that accumulate transmembrane receptors and GFP-Atg8a in ESCRT mutant cells are distinct (Rusten, 2007).

HRP-Lamp1 (HRP: horseradish peroxidase), a marker for late endosomes and lysosomes, colocalizes with GFP-Atg8 in autolysosomes of wild-type larvae. In contrast, in vps25 mutant follicle cells, GFP-Atg8a accumulated in structures distinct from those containing HRP-Lamp1, suggesting a lack of fusion between autophagosomes and endolysosomes in the absence of functional ESCRTs. Because ESCRT mutations affect the trafficking of a number of transmembrane molecules, it remained possible that HRP-Lamp1 was trapped in a biosynthetic compartment and therefore failed to colocalize with GFP-Atg8a. To bypass this problem, Texas Red Dextran (TRD) was used as a fluid-phase endocytic tracer in eye imaginal discs and it was asked whether GFP-Atg8a colocalizea with TRD-containing endosomal and lysosomal compartments. Control discs showed a low basal amount of autophagy with GFP-Atg8a partially colocalizing with TRD-containing late endosomes and lysosomes, indicating the presence of both autophagosomes and amphisomes or autolysosomes. A similar colocalization was observed in L3 fat body cells, which contain more autophagic activity. Similar to follicle and fat body cells, a strong GFP-Atg8a accumulation is observed in mutant discs consisting almost exclusively of vps25 mutant cells. In contrast to the situation in control discs, GFP-Atg8a does not colocalize with TRD in the vps25 mutant cells. This suggests a lack of fusion of endolysosomal and autophagosomal compartments in the mutant cells. The lack of colocalization in vps25 mutant discs was not due to impaired uptake or trafficking because TRD reached structures labeled with HRP-Lamp1. This finding also confirms that HRP-Lamp1 labels endocytic compartments in vps25 mutant cells. Taken together, these results suggest that ESCRT and Vps4 functions are required for the fusion of autophagic structures with the endolysosomal pathway (Rusten, 2007).

In order to characterize the structures accumulating in larvae with impaired ESCRT, Vps4, or Fab1 function at the ultrastructural level, mutant larvae were investigated by electron microscopy, which stringently identifies the presence of autophagosomes. Few autophagic structures were apparent in the fat body cells or the epithelial cells of the gut in L2 larvae. Larvae mutant for vps28 or vps25, in contrast, accumulated massive amounts of autophagosomes in both the gut and fat body. In contrast, no amphisomes or autolysosomes were evident, suggesting that the fusion of autophagsomes with late endosomes and/or lysosomes is defective in the absence of vps28 or vps25. In larvae expressing Vps4DN specifically in the fat body and not in the gut epithelium, a strong accumulation of autophagic structures was apparent in fat body cells only. The Vps4DN-induced autophagic structures were, however, less homogeneous in appearance than those in ESCRT mutant larvae. Although the vast majority of the Vps4DN-induced autophagic structures were clearly autophagosomes, others had morphology consistent with material at various stages of degradation, indicating that some fusion of autophagosomes with endosomes or lysosomes carrying degradative enzymes had occurred. The latter finding suggests a lower penetrance of the Vps4DN phenotype than of ESCRT null mutations and is in agreement with earlier work in which the expression of a mammalian dominant-negative Vps4 homolog, SKD1DN, or the small interfering RNA (siRNA)-mediated depletion of Tsg101 in HeLa cells led to the accumulation of autophagosomes and, to a lesser extent, of autolysosomes (Rusten, 2007).

Distinct from cells whose ESCRT or Vps4 function was compromised, cells lacking fab1 exhibited the accumulation of amphisomes. In eye imaginal discs, these were identified by electron microscopy as vacuolar structures containing endocytosed BSA-gold and undegraded cytoplasmic material. Morphologically similar structures were observed in fab1 mutant gut cells. This result indicates that Fab1 is required for the progression of amphisomes to autolysosomes, paralleling its role in the endosomal system, where Fab1 regulates the maturation of late endosomes into lysosomes (Rusten, 2006; Nicot, 2006). It is speculated that this lack of progression to autolysosomes might be caused by the failure of acidification of the endosomal compartment. Taken together, these data thus suggest that ESCRT, Vps4, and Fab1 act at distinct consecutive steps during basal autophagy. ESCRT and Vps4 functions are necessary for the autophagosome-endolysosome fusion step, whereas Fab1 function is necessary for the maturation of autolysosomes (Rusten, 2007).

Autophagy under nonstarvation conditions is thought to be important for the removal of misfolded proteins from the cytoplasm, and impaired autophagy has therefore been postulated to contribute to neurodegenerative diseases in humans. In support of this model, in mice made specifically defective in autophagy in the central nervous system (CNS), brain cells accumulate polyubiquitinated protein aggregates and die (Hara, 2006; Komatsu, 2006). In addition, reducing autophagy aggravates neurotoxicity in models of Huntington's disease in Drosophila and Caenorhabditis elegans, whereas boosting autophagy can suppress cytotoxicity in these models of polyglutamine-induced protein-aggregate diseases (Rusten, 2007).

Because these data show that ESCRT proteins are required for autophagy, it was asked whether ESCRT proteins have a role in protein-aggregate-induced neurodegeneration by using a Drosophila model for Huntington's disease. The expression of a 120Q polyglutamine expansion protein specifically in the photoreceptors of the developing eye results in a strong reduction in the number of intact photoreceptor neurons. This provides a sensitized system in which the potential role of ESCRT proteins in the removal of toxic proteins from the cytoplasm can be addressed. Interestingly, removing one copy of either vps28, vps25, or vps32 resulted in an increased loss of photoreceptor neurons despite having no toxic effect by itself. It is concluded that ESCRT function might be needed for the autophagic clearance of toxic proteins in the cytoplasm in order to protect against neuronal cell death. This is consistent with a paper published when the present manuscript was under review (Lee, 2007), reporting that impaired ESCRT-III functions cause the death of cultured neurons and the accumulation of autophagosomes (Rusten, 2007).

The findings presented in this study show the cell-autonomous accumulation of autophagosomes in ESCRT mutant cells or in cells expressing Vps4DN. This accumulation is most likely explained by a lack of fusion between autophagosomes and endolysosomal compartments during basal autophagy. Alternatively, it could be an indirect effect of upregulation of proautophagic signaling or a failure in lysosome biogenesis. The first possibility is favored because in ESCRT mutant cells, Hrs-positive sorting endosomes and Lamp1-positive late endosomes or lysosomes were observed, but not their fusion products with autophagosomes. This suggests a specific defect in fusion, and this defect could possibly be explained through interference with SNARE function or the failed recruitment of the HOPS-C complex required for this fusion step in yeast and Drosophila (Lindmo, 2006b: Pulipparacharuvil, 2005; Rusten, 2007 and references therein).

Several recent findings suggest a direct involvement of defective ESCRT function in human neurodegenerative disease. A rare inheritable form of the neurodegenerative disease, frontotemporal dementia (FTD), was recently mapped to a dominant mutation in the ESCRT-III member, CHMP2B/Vps2B. Similarly, CHMP2B mutations were observed in patients suffering from amyotrophic lateral sclerosis (ALS). Motor neurons from affected ALS patients showed protein inclusions labeled with ubiquitin and p62, a protein recently found to be necessary to recruit LC3 (a human Atg8 homolog), suggesting that polyubiquitinated protein aggregates might be tagged for autophagy by p62 in ALS patients or reside in autophagosomes failing to fuse with the endolysosomal pathway. In line with such a model, the accumulation of aggregated ubiquitin-positive structures is seen colocalizing with GFP-Atg8a in Vps4DN-expressing neurons in the larval brain. A further link between ESCRT proteins and neurodegeneration in mammals has been suggested because mice deficient in Mahogunin, an E3 ubiquitin ligase that is necessary for ubiquitination and function of the ESCRT-I subunit, Tsg101, also develop neurodegenerative disease. Strikingly, it was found that reduced ESCRT function leads to aggravated neurotoxicity in a Drosophila Huntington's disease model, thereby providing direct evidence for a neuroprotective role of the ESCRTs. In conclusion, the results presented in this study raise the possibility that components of the endosomal sorting machinery could protect against neurodegenerative disease through their function in autophagy (Rusten, 2007).


Search PubMed for articles about Drosophila Fab1

Berwick, D. C., et al. (2004). Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. J. Cell Sci. 117: 5985-5993. PubMed ID: 15546921

Ellson, C. D., Andrews, S., Stephens, L. R. and Hawkins, P. T. (2002). The PX domain: a new phosphoinositide-binding module. J. Cell Sci. 115: 1099-1105. PubMed ID: 11884510

Hara, T., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885-889. PubMed ID: 16625204

Ikonomov, O. C., Sbrissa, D. and Shisheva, A. (2001). Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve. J. Biol. Chem. 276: 26141-26147. PubMed ID: 11285266

Ikonomov, O. C., Sbrissa, D., Foti, M., Carpentier, J. L. and Shisheva, A. (2003). PIKfyve controls fluid phase endocytosis but not recycling/degradation of endocytosed receptors or sorting of procathepsin D by regulating multivesicular body morphogenesis. Mol. Biol. Cell. 14: 4581-4591. PubMed ID: 14551253

Komatsu, M., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880-884. PubMed ID: 16625205

Lee, J. A., et al. (2007). ESCRT-III Dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17: 1561-1567. PubMed ID: 17683935

Lee, J. A., et al. (2009). Autophagy in neurodegeneration: two sides of the same coin. BMB Rep. 42(6): 324-30. PubMed ID: 19558789

Li, S., et al. (2005). Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy. Am. J. Hum. Genet. 77: 54-63. PubMed ID: 15902656

Lindmo, K. and Stenmark, H. (2006a). Regulation of membrane traffic by phosphoinositide 3-kinases. J. Cell Sci. 119: 605-614. PubMed ID: 16467569

Lindmo, K., et al. (2006b). A dual function for Deep orange in programmed autophagy in the Drosophila melanogaster fat body. Exp. Cell Res. 312: 2018-2027. PubMed ID: 16600212

Nicot, A. S., et al. (2006). The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans. Mol. Biol. Cell 17: 3062-3074. PubMed ID: 16801682

Odorizzi, G., Babst, M. and Emr, S. D. (1998). Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body. Cell 95: 847-858. PubMed ID: 9865702

Pulipparacharuvil, S., et al. (2005). Drosophila Vps16A is required for trafficking to lysosomes and biogenesis of pigment granules. J. Cell Sci. 118: 3663-3673. PubMed ID: 16046475

Rusten, T. E., et al. (2004). Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev. Cell 7: 179-192. PubMed ID: 15296715

Rusten, T. E., et al. (2006). Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors. Mol. Biol. Cell 17(9): 3989-4001. PubMed ID: 16837550

Rusten, T. E., et al. (2007). ESCRTs and Fab1 regulate distinct steps of autophagy. Curr. Biol. 17(20): 1817-25. PubMed ID: 17935992

Scott, R. C., Schuldiner, O. and Neufeld, T. P. (2004). Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7: 167-178. PubMed ID: 15296714

Sevrioukov, E. A., Moghrabi, N., Kuhn, M. and Kramer, H. (2005). A mutation in dVps28 reveals a link between a subunit of the endosomal sorting complex required for transport-I complex and the actin cytoskeleton in Drosophila. Mol. Biol. Cell 16: 2301-2312. PubMed ID: 15728719

Stenmark, H., Aasland, R. and Driscoll, P. C. (2002). The phosphatidylinositol 3-phosphate-binding FYVE finger. FEBS Lett. 513: 77-84. PubMed ID: 11911884

Vaccari, T. and Bilder, D. (2005). The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev. Cell 9: 687-698. PubMed ID: 16256743

Biological Overview

date revised: 30 November 2009

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