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111.
The type I phosphatidylinositol 4-phosphate 5-kinases (PI4P5K) phosphorylate phosphatidylinositol 4-phosphate [PI(4)P] to produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. PI(4,5)P2 has been implicated in signal transduction, receptor mediated endocytosis, vesicle trafficking, cytoskeletal structure, and membrane ruffling. However, the specific type I enzymes associated with the production of PI(4,5)P2 for the specific cellular processes have not been rigorously defined. Murine PI4P5K type Ibeta (mPIP5K-Ibeta) was implicated in receptor mediated endocytosis through the isolation of a truncated and inactive form of the enzyme that blocked the ligand-dependent downregulation of the colony-stimulating factor-1 receptor. The present study shows that enforced expression of mPIP5K-Ibeta in 293T cells resulted in the accumulation of large vesicles that were linked to an endosomal pathway. Similar results were obtained after the expression of the PI(4,5)P2-binding pleckstrin homology (PH) domain of phospholipase-Cdelta (PLC-delta). Analysis of the conserved domains of mPIP5K-Ibeta led to the identification of dimerization domains in the N- and C-terminal regions. Enforced expression of the individual dimerization domains interfered with the proper subcellular localization of mPIP5K-Ibeta and the PLC-delta-PH domain and blocked the accumulation of the endocytic vesicles induced by these proteins. In addition to regulating early steps in endocytosis, these results suggest that mPIP5K-Ibeta acts through PI(4,5)P2 to regulate endosomal trafficking and/or fusion. 相似文献
112.
Changes in dendritic cell migration and activation during SIV infection suggest a role in initial viral spread and eventual immunosuppression 总被引:1,自引:0,他引:1
Dendritic cells (DC) serve an essential function in linking the innate and acquired immune responses to antigen. Peripheral DC acquire antigen and migrate to draining lymph nodes, where they localize to the T cell-rich paracortex and function as potent antigen presenting cells. We examined the effects of human immunodeficiency virus (HIV) infection on DC function in vivo using the rhesus macaque/simian immunodeficiency virus (SIV) model. Our data show that during acute SIV infection, Langerhans cell density is reduced in skin and activated DC are increased in proportion in lymph nodes, whereas during AIDS, DC migration from skin and activation within lymph nodes are suppressed. These findings suggest that changes in DC function at different times during the course of infection may serve to promote virus dissemination and persistence: early during infection, DC mobilization may facilitate virus spread to susceptible lymph node T cell populations, whereas depressed DC function during advanced infection could promote generalized immunosuppression. 相似文献
113.
The Menkes copper-translocating P-type ATPase (ATP7A; MNK) is a ubiquitous protein that regulates the absorption of copper in the gastrointestinal tract. Inside cells the protein has a dual function: it delivers copper to cuproenzymes in the Golgi compartment and effluxes excess copper. The latter property is achieved through copper-dependent vesicular trafficking of the Menkes protein to the plasma membrane of the cell. The trafficking mechanism and catalytic activity combine to facilitate absorption and intercellular transport of copper. The mechanism of catalysis and copper-dependent trafficking of the Menkes protein are the subjects of this review. Menkes disease, a systemic copper deficiency disorder, is caused by mutations in the gene encoding the Menkes protein. The effect of these mutations on the catalytic cycle and the cell biology of the Menkes protein, as well as predictions of the effect of particular mutant MNKs on observed Menkes disease symptoms will also be discussed. 相似文献
114.
115.
Giardia lamblia: identification and characterization of Rab and GDI proteins in a genome survey of the ER to Golgi endomembrane system 总被引:4,自引:0,他引:4
Langford TD Silberman JD Weiland ME Svärd SG McCaffery JM Sogin ML Gillin FD 《Experimental parasitology》2002,101(1):13-24
To investigate the complexity of the endomembrane transport system in the early diverging eukaryote, Giardia lamblia, we characterized homologues of the GTP-binding proteins, Rab1 and Rab2, involved in regulating vesicular trafficking between the endoplasmic reticulum and Golgi in higher eukaryotes, and GDI, which plays a key role in the cycling of Rab proteins. G. lamblia Rab1, 2.1, and GDI sequences largely resemble yeast and mammalian homologues, are transcribed as 0.66-, 0.62-, and 1.4-kb messages, respectively, and are expressed during growth and encystation. Western analyses detected an abundant Rab/GDI complex at approximately 80 kDa, and free GDI (60 kDa) in both trophozoites and encysting cells. Immunoelectron microscopy with antibody to Rab1 localized Rab with ER, encystation secretory vesicles, and lysosome-like peripheral vesicles. GDI associated with these structures, and with small vesicles found throughout the cytoplasm, consistent with GDI's key role in Rab cycling between organelles within the cell. 相似文献
116.
Ca(2+) and Mg(2+)/ATP independently trigger homotypic membrane fusion in gastric secretory membranes
Exocytic activation of gastric parietal cells represents a massive transformation. We studied a step in this process, homotypic fusion of H,K-ATPase-containing tubulovesicles, using R18 dequenching. Ca2+ and Mg2+ /ATP each caused dramatic dequenching, reflecting a change in R18 distribution from 5% to 65–90% of the assay's membranes in 2.5 min. These stimuli also triggered fusion between tubulovesicles and liposomes. Independent confirmation that dequenching represented membrane fusion was established by separating tubulovesicle–liposome fusion products on density gradients. Only agents that trigger fusion allowed the transmembrane H,K-ATPase to move to low-density fractions along with R18. EC50 for Ca2+ -triggered fusion was 150 n m and for Mg2+ /ATP-triggered fusion 1 m m , the latter having a Hill coefficient of 2.5. ATP-triggered fusion was specific for Mg2+ /ATP, required ATP hydrolysis, and was insensitive to inhibition of NSF and/or H,K-ATPase. Fusion initiated by either trigger caused tubulovesicles to become resistant to subsequent challenge by either trigger. Ca2+ -and Mg2+ /ATP-triggered fusion required protein component(s) in tubulovesicles, though this was required in only one of the fusing membranes since tubulovesicles fused well with liposomes containing no proteins. Our data suggest that exocytosis in parietal cells is triggered by separate but interacting pathways and is regulated by self-inhibition. 相似文献
117.
Ahn K Yeyeodu S Collette J Madden V Arthur J Li L Erickson AH 《Traffic (Copenhagen, Denmark)》2002,3(2):147-159
In transformed mouse fibroblasts, a significant proportion of the lysosomal cysteine protease cathepsin L remains in cells as an inactive precursor which associates with membranes by a mannose phosphate-independent interaction. When microsomes prepared from these cells were resolved on sucrose gradients, this procathepsin L was localized in dense vesicles distinct from those enriched for growth hormone, which is secreted constitutively when expressed in fibroblasts. Ultrastructural studies using antibodies directed against the propeptide to avoid detection of the mature enzyme in lysosomes revealed that the proenzyme was concentrated in dense cores within small vesicles and multivesicular endosomes which labeled with antibodies specific for CD63. Consistent with the resemblance of these cores to those of regulated secretory granules, secretion of procathepsin L from fibroblasts was modestly stimulated by phorbol, 12-myristate, 13-acetate. When protein synthesis was blocked with cycloheximide and lysosomal proteolysis inhibited with leupeptin, procathepsin L was found to gradually convert to the active single-chain protease. The data suggest that when synthesis levels are high, a portion of the procathepsin L is packaged in dense cores within multivesicular endosomes localized near the plasma membrane. Gradual activation of this proenzyme achieves targeting of the proenzyme to lysosomes by a mannose phosphate receptor-independent pathway. 相似文献
118.
Nurrish SJ 《Traffic (Copenhagen, Denmark)》2002,3(1):2-10
It is almost 40 years since Sydney Brenner introduced Caenorhabditis elegans as a model genetic system. During that time mutants with defects in intracellular trafficking have been identified in a diverse range of screens for abnormalities. This should, of course, come as no surprise as it is hard to imagine any biological process in which the regulated movement of vesicles within the cells is not critical at some step. Almost all of these genes have mammalian homologs, and yet the role of many of these homologs has not been investigated. Perhaps the protein that regulates your favorite trafficking step has already been identified in C. elegans? Here I provide a brief overview of those trafficking mutants identified in C. elegans and where you can read more about them. 相似文献
119.
Some cultured cells contain significant amounts of a rarely recognized phospholipid, phosphatidylthreonine. Since phosphatidylthreonine is a structural analog of phosphatidylserine, the question rises whether it is transported to mitochondria and decarboxylated to phosphatidylisopropanolamine therein. We studied this issue with hamster kidney cell-line using a novel approach, i.e. electrospray mass-spectrometry and stable isotope-labeled precursors. Scanning for a neutral loss of 155, which is characteristic for phosphatidylisopropanolamine, indicated that this lipid is indeed present. The identity of phosphatidylisopropanolamine was supported by the following: (i) it co-chromatographed with phosphatidylethanolamine; (ii) its molecular species profile was similar to that of phosphatidylethanolamine; (iii) its head group was labeled from 13 C-threonine; and (iv) its concentration increased in parallel with phosphatidylthreonine. Tests with solubilized decarboxylase and subcellular fractionation studies indicated that the low cellular content of phosphatidylisopropanolamine is due to inefficient decarboxylation, rather than poor translocation of phosphatidylthreonine to mitochondria. Importantly, the average hydrophobicity of phosphatidylisopropanolamine molecular species was significantly less than that of phosphatidylthreonine species, indicating that hydrophilic phosphatidylthreonine species translocate to mitochondria far more rapidly than hydrophobic ones. Parallel results were obtained for phosphatidylserine. These findings imply that efflux from the ER membrane could be the rate-limiting step in the phosphatidylthreonine and -serine translocation to mitochondria. 相似文献
120.
Wood CM McDonald MD Sundin L Laurent P Walsh PJ 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2003,136(4):667-684
Opsanus beta expresses a full complement of ornithine–urea cycle (OUC) enzymes and is facultatively ureotelic, reducing ammonia-N excretion and maintaining urea-N excretion under conditions of crowding/confinement. The switch to ureotelism is keyed by a modest rise in cortisol associated with a substantial increase in cytosolic glutamine synthetase for trapping of ammonia-N and an upregulation of the capacity of the mitochondrial OUC to use glutamine-N. The entire day's urea-N production is excreted in 1 or 2 short-lasting pulses, which occur exclusively through the gills. The pulse event is not triggered by an internal urea-N threshold, is not due to pulsatile urea-N production, but reflects pulsatile activation of a specific branchial excretion mechanism that rapidly clears urea-N from the body fluids. A bidirectional facilitated diffusion transporter, with pharmacological similarity to the UT-A type transporters of the mammalian kidney, is activated in the gills, associated with an increased trafficking of dense-cored vesicles in the pavement cells. An 1814 kB cDNA (‘tUT’) coding for a 475–amino acid protein with approximately 62% homology to mammalian UT-A's has been cloned and facilitates phloretin-sensitive urea transport when expressed in Xenopus oocytes. tUT occurs only in gill tissue, but tUT mRNA levels do not change over the pulse cycle, suggesting that tUT regulation occurs at a level beyond mRNA. Circulating cortisol levels consistently decline prior to a pulse event and rise thereafter. When cortisol is experimentally clamped at high levels, natural pulse events are suppressed in size but not in frequency, an effect mediated through glucocorticoid receptors. The cortisol decline appears to be permissive, rather than the actual trigger of the pulse event. Fluctuations in circulating AVT levels do not correlate with pulses; and injections of AVT (at supraphysiological levels) elicit only minute urea-N pulses. However, circulating 5-hydroxytryptamine (5-HT) levels fluctuate considerably and physiological doses of 5-HT cause large urea-N pulse events. When the efferent cranial nerves to the gills are sectioned, natural urea pulse events persist, suggesting that direct motor output from the CNS to the gill is not the proximate control. 相似文献