Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BAR adaptor proteins encoded by the RVS167 and RVS161 genes from Saccharomyces cerevisiae form a complex that regulates actin, endocytosis, and viability following starvation or osmotic stress. In this study, we identified a human homolog of RVS161, termed BIN3 (bridging integrator-3), and a Schizosaccharomyces pombe homolog of RVS161, termed hob3+ (homolog of Bin3). In human tissues, the BIN3 gene was expressed ubiquitously except for brain. S. pombe cells lacking Hob3p were often multinucleate and characterized by increased amounts of calcofluor-stained material and mislocalized F-actin. For example, while wild-type cells localized F-actin to cell ends during interphase, hob3Delta mutants had F-actin patches distributed randomly around the cell. In addition, medial F-actin rings were rarely found in hob3Delta mutants. Notably, in contrast to S. cerevisiae rvs161Delta mutants, hob3Delta mutants showed no measurable defects in endocytosis or response to osmotic stress, yet hob3+ complemented the osmosensitivity of a rvs161Delta mutant. BIN3 failed to rescue the osmosensitivity of rvs161Delta, but the actin localization defects of hob3Delta mutants were completely rescued by BIN3 and partially rescued by RVS161. These findings suggest that hob3+ and BIN3 regulate F-actin localization, like RVS161, but that other roles for this gene have diverged somewhat during evolution.
 ...
PMID:Human BIN3 complements the F-actin localization defects caused by loss of Hob3p, the fission yeast homolog of Rvs161p. 1127 58

BAR (Bin/Amphiphysin/Rvs) adapter proteins have been suggested to regulate endocytosis, actin organization, apoptosis, and transcription, but their precise roles are obscure. There are at least five mammalian genes that encode BAR adapter proteins, including the evolutionarily conserved and ubiquitously expressed Bin1/Amphiphysin-II and Bin3 genes. Bin1 holds special interest as certain splice isoforms localize to the nucleus, interact with the c-Abl and c-Myc oncoproteins, and display tumor suppressor properties. To obtain functional insights, we embarked upon a genetic analysis of the two BAR adapter proteins expressed in the fission yeast Schizosaccharomyces pombe. In a previous work, a role in actin organization and cytokinesis was identified for the Bin3 homolog hob3+. In this study, a role in stress signaling was defined for the Bin1 homolog, hob1+. Notably, hob1+ was dispensable for endocytosis, actin organization, or osmotic sensitivity. Instead, mutation of hob1+ led to slight cell elongation and faulty cell cycle arrest upon nutrient starvation. These defects were complemented by Bin1, but not by Amphiphysin-I, arguing that these genes have distinct functions despite their structural similarity. hob1 delta mutant cells were also hypersensitive to genotoxic stress. This was not related to a faulty checkpoint response, but mutation in the checkpoint gene rad3(+) further exacerbated the sensitivity of hob1 delta mutant cells. Interestingly, mutation of the cell cycle regulator wee1+ partially relieved the sensitivity defect, suggesting that hob1+ may influence the efficiency of DNA repair or checkpoint release after DNA damage. Genetic and biochemical evidence indicated that hob3+ is epistatic to hob1+ in the response to genotoxic stress. Our findings indicate that the Bin1 homolog hob1+ participates in DNA damage signaling and they suggest a novel role for BAR adapter proteins in stress response processes.
 ...
PMID:hob1+, the fission yeast homolog of Bin1, is dispensable for endocytosis or actin organization, but required for the response to starvation or genotoxic stress. 1256 56

Autophagy is an evolutionarily conserved 'self-eating' process. Although the genes essential for autophagy (named Atg) have been identified in yeast, the molecular mechanism of how Atg proteins control autophagosome formation in mammalian cells remains to be elucidated. Here, we demonstrate that Bif-1 (also known as Endophilin B1) interacts with Beclin 1 through ultraviolet irradiation resistance-associated gene (UVRAG) and functions as a positive mediator of the class III PI(3) kinase (PI(3)KC3). In response to nutrient deprivation, Bif-1 localizes to autophagosomes where it colocalizes with Atg5, as well as microtubule-associated protein light chain 3 (LC3). Furthermore, loss of Bif-1 suppresses autophagosome formation. Although the SH3 domain of Bif-1 is sufficient for binding to UVRAG, both the BAR and SH3 domains are required for Bif-1 to activate PI(3)KC3 and induce autophagosome formation. We also observed that Bif-1 ablation prolongs cell survival under starvation conditions. Moreover, knockout of Bif-1 significantly enhances the development of spontaneous tumours in mice. These findings suggest that Bif-1 joins the UVRAG-Beclin 1 complex as a potential activator of autophagy and tumour suppressor.
 ...
PMID:Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. 1790 25

Yeast cells undergoing a nutritional shift-up from a poor to a rich carbon source take several hours to adapt to the novel, richer carbon source. The budding index is a physiologically relevant "global" parameter that reflects the complex links between cell growth and division that are both coordinately and deeply affected by nutritional conditions. We used changes in budding index as a guide to choose appropriate, relevant time points during an ethanol to glucose nutritional shift-up for preparation of samples for the analysis of proteome by two-dimensional electrophoresis/mass spectrometry. About 600 spots were detected. 90 spots, mostly comprising proteins involved in intermediary metabolism, protein synthesis, and response to stress, showed differential expression after glucose addition. Among modulated proteins we identified a protein of previously unknown function, Gvp36, showing a transitory increase corresponding to the drop of the fraction of budded cells. A gvp36Delta strain shares several phenotypes (including general growth defects, heat shock, and high salt sensitivity, defects in polarization of the actin cytoskeleton, in endocytosis and in vacuolar biogenesis, defects in entering stationary phase upon nutrient starvation) with secretory pathway mutants and with mutants in genes encoding the two previously known yeast BAR proteins (RSV161 and RSV167). We thus propose that Gvp36 represents a novel yeast BAR protein involved in vesicular traffic and in nutritional adaptation.
 ...
PMID:Proteomic analysis of a nutritional shift-up in Saccharomyces cerevisiae identifies Gvp36 as a BAR-containing protein involved in vesicular traffic and nutritional adaptation. 1815 77

Autophagy is an intracellular bulk degradation system that plays a vital role in maintaining cellular homeostasis. This degradation process involves dynamic membrane rearrangements resulting in the formation of double-membraned autophagosomes. However, the driving force for generating curvature and deformation of isolation membranes remains a mystery. Bax-interacting factor 1 (Bif-1), also known as SH3GLB1 or Endophilin B1, was originally discovered as a Bax-binding protein. Bif-1 contains an amino-terminal N-BAR (Bin-Amphiphysin-Rvs) domain and a carboxy-terminal SH3 (Src-homology 3) domain and shows membrane binding and bending activities. It has been shown that Beclin1 is involved in the nucleation of autophagosomal membranes through an unknown mechanism. It is interesting that, Bif-1 forms a complex with Beclin1 through ultraviolet irradiation resistant-associated gene (UVRAG) and promotes the activation of the class III PI3 kinase, Vps34, in mammalian cells. In response to nutrient starvation, Bif-1 accumulates in punctate foci where it co-localizes with LC3, Atg5, and Atg9. Furthermore, Bif-1-positive, crescent-shaped small vesicles expand by recruiting and fusing with Atg9-positive small membranes to complete autophagosome formation. This review highlights the role of Bif-1 in the regulation of autophagy and discusses the potential involvement of Bif-1 in the biogenesis of membranes for the formation of autophagosomes.
 ...
PMID:Bif-1/endophilin B1: a candidate for crescent driving force in autophagy. 1926 52

Amphiphysins are proteins thought to be involved in synaptic vesicle endocytosis. Amphiphysins share a common BAR domain, which can sense and/or bend membranes, and this function is believed to be essential for endocytosis. Saccharomyces cerevisiae cells lacking the amphiphysin ortholog Rvs161 are inviable when starved for glucose. Altering sphingolipid levels in rvs161 cells remediates this defect, but how lipid changes suppress remains to be elucidated. Here, we show that the sugar starvation-induced death of rvs161 cells extends to other fermentable sugar carbon sources, and the loss of sphingolipid metabolism suppresses these defects. In all cases, rvs161 cells respond to the starvation signal, elicit the appropriate transcriptional response, and properly localize the requisite sugar transporter(s). However, Rvs161 is required for transporter endocytosis. rvs161 cells accumulate transporters at the plasma membrane under conditions normally resulting in their endocytosis and degradation. Transporter endocytosis requires the endocytosis (endo) domain of Rvs161. Altering sphingolipid metabolism by deleting the very-long-chain fatty acid elongase SUR4 reinitiates transporter endocytosis in rvs161 and rvs161 endo(-) cells. The sphingolipid-dependent reinitiation of endocytosis requires the ubiquitin-regulating factors Doa1, Doa4, and Rsp5. In the case of Doa1, the phospholipase A(2) family ubiquitin binding motif is dispensable. Moreover, the conserved AAA-ATPase Cdc48 and its accessory proteins Shp1 and Ufd1 are required. Finally, rvs161 cells accumulate monoubiquitin, and this defect is remediated by the loss of SUR4. These results show that defects in sphingolipid metabolism result in the reinitiation of ubiquitin-dependent sugar transporter endocytosis and suggest that this event is necessary for suppressing the nutrient starvation-induced death of rvs161 cells.
 ...
PMID:Altering sphingolipid metabolism in Saccharomyces cerevisiae cells lacking the amphiphysin ortholog Rvs161 reinitiates sugar transporter endocytosis. 1928 82

Autophagy is a conserved cellular process required for the removal of defective organelles, protein aggregates, and intracellular pathogens. We used a network analysis strategy to identify novel human autophagy components based upon the yeast interactome centered on the core yeast autophagy proteins. This revealed the potential involvement of 14 novel mammalian genes in autophagy, several of which have known or predicted roles in membrane organization or dynamics. We selected one of these membrane interactors, FNBP1L (formin binding protein 1-like), an F-BAR-containing protein (also termed Toca-1), for further study based upon a predicted interaction with ATG3. We confirmed the FNBP1L/ATG3 interaction biochemically and mapped the FNBP1L domains responsible. Using a functional RNA interference approach, we determined that FNBP1L is essential for autophagy of the intracellular pathogen Salmonella enterica serovar Typhimurium and show that the autophagy process serves to restrict the growth of intracellular bacteria. However, FNBP1L appears dispensable for other forms of autophagy induced by serum starvation or rapamycin. We present a model where FNBP1L is essential for autophagy of intracellular pathogens and identify FNBP1L as a differentially used molecule in specific autophagic contexts. By using network biology to derive functional biological information, we demonstrate the utility of integrated genomics to novel molecule discovery in autophagy.
 ...
PMID:A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy. 1934 71

Atg9 is a transmembrane protein essential for autophagy which cycles between the Golgi network, late endosomes and LC3-positive autophagosomes in mammalian cells during starvation through a mechanism that is dependent on ULK1 and requires the activity of the class III phosphatidylinositol-3-kinase (PI3KC3). In this study, we demonstrate that the N-BAR-containing protein, Bif-1, is required for Atg9 trafficking and the fission of Golgi membranes during the induction of autophagy. Upon starvation, Atg9-positive membranes undergo continuous tubulation and fragmentation to produce cytoplasmic punctate structures that are positive for Rab5, Atg16L and LC3. Loss of Bif-1 or inhibition of the PI3KC3 complex II suppresses starvation-induced fission of Golgi membranes and peripheral cytoplasmic redistribution of Atg9. Moreover, Bif-1 mutants, which lack the functional regions of the N-BAR domain that are responsible for membrane binding and/or bending activity, fail to restore the fission of Golgi membranes as well as the formation of Atg9 foci and autophagosomes in Bif-1-deficient cells starved of nutrients. Taken together, these findings suggest that Bif-1 acts as a critical regulator of Atg9 puncta formation presumably by mediating Golgi fission for autophagosome biogenesis during starvation.
 ...
PMID:Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy. 2106 42

Autophagy cargos include not only soluble cytosolic materials but also bulky organelles, such as ER and mitochondria. In budding yeast, two proteins that contain the PX domain and the BAR domain, Atg20 and Atg24 (also known as Snx42 and Snx4, respectively) are required for organelle autophagy and contribute to general autophagy in a way that can be masked by compensatory mechanisms. It remains unclear why these proteins are important for organelle autophagy. Here, we show that in a distantly related fungal organism, the fission yeast Schizosaccharomyces pombe, autophagy of ER and mitochondria is induced by nitrogen starvation and is promoted by three Atg20- and Atg24-family proteins - Atg20, Atg24 and SPBC1711.11 (named here as Atg24b). These proteins localize at the pre-autophagosomal structure, or phagophore assembly site (PAS), during starvation. S. pombe Atg24 forms a homo-oligomer and acts redundantly with Atg20 and Atg24b, and the latter two proteins can form a hetero-oligomer. The organelle autophagy defect caused by the loss of these proteins is associated with a reduction of autophagosome size and a decrease in Atg8 accumulation at the PAS. These results provide new insights into the autophagic function of Atg20- and Atg24-family proteins.
 ...
PMID:Atg20- and Atg24-family proteins promote organelle autophagy in fission yeast. 2773 12

The eukaryotic plasma membrane is compartmentalized into domains enriched in specific lipids and proteins. However, our understanding of the molecular bases and biological roles of this partitioning remains incomplete. The best-studied domain in yeast is the membrane compartment containing the arginine permease Can1 (MCC) and later found to cluster additional transporters. MCCs correspond to static, furrow-like invaginations of the plasma membrane and associate with subcortical structures named "eisosomes" that include upstream regulators of the target of rapamycin complex 2 (TORC2) in the sensing of sphingolipids and membrane stress. However, how and why Can1 and other nutrient transporters preferentially segregate in MCCs remains unknown. In this study we report that the clustering of Can1 in MCCs is dictated by its conformation, requires proper sphingolipid biosynthesis, and controls its ubiquitin-dependent endocytosis. In the substrate-free outward-open conformation, Can1 accumulates in MCCs in a manner dependent on sustained biogenesis of complex sphingolipids. An arginine transport-elicited shift to an inward-facing conformation promotes its cell-surface dissipation and makes it accessible to the ubiquitylation machinery triggering its endocytosis. We further show that under starvation conditions MCCs increase in number and size, this being dependent on the BAR domain-containing Lsp1 eisosome component. This expansion of MCCs provides protection for nutrient transporters from bulk endocytosis occurring in parallel with autophagy upon TORC1 inhibition. Our study reveals nutrient-regulated protection from endocytosis as an important role for protein partitioning into membrane domains.
 ...
PMID:Conformation-dependent partitioning of yeast nutrient transporters into starvation-protective membrane domains. 2955 31


1 2 Next >>