(searched for: doi:10.1042/bss0740259)
Published: 20 October 2012
Phosphatidylinositol transfer proteins (PITPs), comprising five members in the human genome are implicated in the non-vesicular traffic of phosphatidylinositol (PI) between intracellular membranes and the plasma membrane. Three members of the PITP family (PITPα, PITPβ, and RdgBβ (retinal degeneration type B) alt. name PITPNC1) are present as single domain proteins and two (RdgBαI and RdgBαII alt. name PITPNM1 and PITPNM2) are present as multi-domain proteins with the PITP domain located at the N-terminus. The hallmark of PITP proteins is to extract PI molecules from a membrane, sequester in its binding pocket and deposit the lipid to membranes. PITPs regulate the synthesis of phosphoinositides (PPIs) either by delivery of the substrate, PI to specific membrane compartments or by potentiating the activities of the lipid kinases, or both. In the light of recent studies, we propose that PITPs are regulators of phosphoinositide pathways by recruitment to membranes through specific protein interactions to promote molecular exchange between closely opposed membranes i.e., at membrane contact sites. Individual PITP proteins play highly specific roles in many biological processes including neurite outgrowth, membrane traffic, cytokinesis, and sensory transduction in mammals as well as in the model organisms, Drosophila,Caenorhabditis elegans, and zebrafish. The common requirement for the diverse functions for all PITPs is their ability to bind PI and coupling its function to phosphoinositide-dependent pathways.
Journal of cell science, Volume 123, pp 1262-1273; https://doi.org/10.1242/jcs.061986
Vesicles formed by the COPI complex function in retrograde transport from the Golgi to the endoplasmic reticulum (ER). Phosphatidylinositol transfer protein β (PITPβ), an essential protein that possesses phosphatidylinositol (PtdIns) and phosphatidylcholine (PtdCho) lipid transfer activity is known to localise to the Golgi and ER but its role in these membrane systems is not clear. To examine the function of PITPβ at the Golgi-ER interface, RNA interference (RNAi) was used to knockdown PITPβ protein expression in HeLa cells. Depletion of PITPβ leads to a decrease in PtdIns(4)P levels, compaction of the Golgi complex and protection from brefeldin-A-mediated dispersal to the ER. Using specific transport assays, we show that anterograde traffic is unaffected but that KDEL-receptor-dependent retrograde traffic is inhibited. This phenotype can be rescued by expression of wild-type PITPβ but not by mutants defective in docking, PtdIns transfer and PtdCho transfer. These data demonstrate that the PtdIns and PtdCho exchange activity of PITPβ is essential for COPI-mediated retrograde transport from the Golgi to the ER.
Published: 1 January 2010
Published: 31 October 2009
The international journal of biochemistry & cell biology, Volume 41, pp 1805-1816; https://doi.org/10.1016/j.biocel.2009.02.017
Several recent works show structurally and functionally dynamic contacts between mitochondria, the plasma membrane, the endoplasmic reticulum, and other subcellular organelles. Many cellular processes require proper cooperation between the plasma membrane, the nucleus and subcellular vesicular/tubular networks such as mitochondria and the endoplasmic reticulum. It has been suggested that such contacts are crucial for the synthesis and intracellular transport of phospholipids as well as for intracellular Ca2+ homeostasis, controlling fundamental processes like motility and contraction, secretion, cell growth, proliferation and apoptosis. Close contacts between smooth sub-domains of the endoplasmic reticulum and mitochondria have been shown to be required also for maintaining mitochondrial structure. The overall distance between the associating organelle membranes as quantified by electron microscopy is small enough to allow contact formation by proteins present on their surfaces, allowing and regulating their interactions. In this review we give a historical overview of studies on organelle interactions, and summarize the present knowledge and hypotheses concerning their regulation and (patho)physiological consequences.
Traffic, Volume 9, pp 1743-1756; https://doi.org/10.1111/j.1600-0854.2008.00794.x
Of many lipid transfer proteins identified, all have been implicated in essential cellular processes, but the activity of none has been demonstrated in intact cells. Among these, phosphatidylinositol transfer proteins (PITP) are of particular interest as they can bind to and transfer phosphatidylinositol (PtdIns) – the precursor of important signalling molecules, phosphoinositides – and because they have essential functions in neuronal development (PITPα) and cytokinesis (PITPβ). Structural analysis indicates that, in the cytosol, PITPs are in a ‘closed’ conformation completely shielding the lipid within them. But during lipid exchange at the membrane, they must transiently ‘open’. To study PITP dynamics in intact cells, we chemically targeted their C95 residue that, although non‐essential for lipid transfer, is buried within the phospholipid‐binding cavity, and so, its chemical modification prevents PtdIns binding because of steric hindrance. This treatment resulted in entrapment of open conformation PITPs at the membrane and inactivation of the cytosolic pool of PITPs within few minutes. PITP isoforms were differentially inactivated with the dynamics of PITPβ faster than PITPα. We identify two tryptophan residues essential for membrane docking of PITPs.
Journal of cell science, Volume 121, pp 1955-1963; https://doi.org/10.1242/jcs.023630
The phosphoinositides (PIs) are membrane phospholipids that actively operate at membrane-cytosol interfaces through the recruitment of a number of effector proteins. In this context, each of the seven different PI species represents a topological determinant that can establish the nature and the function of the membrane where it is located. Phosphatidylinositol 4-phosphate (PtdIns(4)P) is the most abundant of the monophosphorylated inositol phospholipids in mammalian cells, and it is produced by D-4 phosphorylation of the inositol ring of PtdIns. PtdIns(4)P can be further phosphorylated to PtdIns(4,5)P2 by PtdIns(4)P 5-kinases and, indeed, PtdIns(4)P has for many years been considered to be just the precursor of PtdIns(4,5)P2. Over the last decade, however, a large body of evidence has accumulated that shows that PtdIns(4)P is, in its own right, a direct regulator of important cell functions. The subcellular localisation of the PtdIns(4)P effectors initially led to the assumption that the bulk of this lipid is present in the membranes of the Golgi complex. However, the existence and physiological relevance of `non-Golgi pools' of PtdIns(4)P have now begun to be addressed. The aim of this Commentary is to describe our present knowledge of PtdIns(4)P metabolism and the molecular machineries that are directly regulated by PtdIns(4)P within and outside of the Golgi complex.
Phytomedicine, Volume 15, pp 268-276; https://doi.org/10.1016/j.phymed.2007.11.015
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