The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling

doi:10.1016/j.tibs.2009.10.008

Trends in Biochemical Sciences

Volume 35, Issue 3, March 2010, Pages 150-160

https://doi.org/10.1016/j.tibs.2009.10.008 Get rights and content

Lipid signaling pathways define central mechanisms for cellular regulation. Productive lipid signaling requires an orchestrated coupling between lipid metabolism, lipid organization and the action of protein machines that execute appropriate downstream reactions. Using membrane trafficking control as primary context, we explore the idea that the Sec14-protein superfamily defines a set of modules engineered for the sensing of specific aspects of lipid metabolism and subsequent transduction of ‘sensing’ information to a phosphoinositide-driven ‘execution phase’. In this manner, the Sec14 superfamily connects diverse territories of the lipid metabolome with phosphoinositide signaling in a productive ‘crosstalk’ between these two systems. Mechanisms of crosstalk, by which non-enzymatic proteins integrate metabolic cues with the action of interfacial enzymes, represent unappreciated regulatory themes in lipid signaling.

Section snippets

Lipids and pathways for membrane trafficking

The identities of proteins that regulate the membrane deformations required for biogenesis and fusion of transport vesicles were discovered by the pioneering studies of Rothman and Schekman some 25 years ago [reviewed in refs 1, 2]. Those descriptions of the vesicle cycle conceptualized protein-centric points of view. That lipid metabolism must be considered as integral participant in mechanistic descriptions of the vesicle cycle first came from studies in permeabilized adrenal chromaffin cells

Lipid platforms

Present discussions of the roles for lipids in control of membrane trafficking are dominated by the well-established concepts that lipids form binding platforms for proteins with quasi-specific lipid-binding motifs [reviewed in 41]. Particular attention in this context has been paid to PIPs, whose binding motifs, including pleckstrin-homology (PH) domains, exhibit rather promiscuous preferences for PtdIns-4,5-P₂, PtdIns-4-P and 3-OH PIPs. In addition, the structurally unrelated FYVE domains,

Lipid transfer proteins: in vitro veritas?

Lipid transfer proteins (LTPs) are not enzymes; therefore operational assays for their activities are denied the clarity of interpreting biological outcomes for chemical conversion of defined substrate to specific product. This presents conceptual difficulties in connecting LTP biochemical assays with functional insights. Nonetheless, mechanisms for LTP (and PITP) function are interpreted in the historical context by which LTPs were first identified in vitro. For PITPs, in vitro transfer assays

The Sec14p tale as told by cells

Genetic studies in yeast have proven invaluable in setting a conceptual framework for what biological activities are responsive to the function of Sec14p and other Sec14-like PITPs, and how these PITPs execute biological function. In what is arguably the best understood case for transfer protein function, four lines of evidence are not particularly congruent with classical transfer mechanisms for Sec14p function.

First, Sec14p levels are around 100-fold above the cellular threshold for viability

The Sec14 superfamily

The Sec14 domain (SMART entry: smart00516), for which the yeast Sec14p is the prototype [54], represents an ancient and versatile structural unit invented by eukaryotes. There are 1551 Sec14 domains, representing 1550 proteins, annotated in the NCBI database (www.ncbi.nlm.nih.gov). Even simple eukaryotes express multiple Sec14 family members. Indeed, Saccharomyces cerevisiae expresses five Sec14-like proteins in addition to Sec14p [55], and Homo sapiens, Mus musculus, Drosophila melanogaster,

Ligand binding by Sec14-like proteins

Available crystal structures of Sec14-like proteins include detergent-bound forms of Sec14p (53,54), several phospholipid-bound forms of yeast Sfh1p, the protein most similar to Sec14p [25], ligand-bound and apo-versions of α-tocopherol transfer protein (α-TTP), the mammalian Sec14-GOLD protein Sec14L2 82, 83, 84, and detergent-bound and phospholipid-bound forms of the neurofibromin Sec14-like domain 85, 86. This ensemble of structures shows that Sec14 domains adopt similar folds – termed the

Coincidence sensors that couple lipid metabolic inputs to PIP synthesis

The differential PtdIns versus PtdCho binding strategies of Sec14p and Sfh1p are revealing. Both PtdIns- and PtdCho-binding activities must reside on the same Sec14p molecule to generate a biologically functional protein that productively stimulates PtdIns 4-OH kinase activity [25]. Thus, heterotypic exchange reactions are required for Sec14p-mediated stimulation of PtdIns kinases (and PIP synthesis) in vivo, indicating that Sec14p cannot stimulate PtdIns 4-OH kinases in cells unless sufficient

Instructive mechanisms for regulating PtdIns-kinase activity

Can a physical picture to be drawn to illustrate how Sec14-like PITPs potentiate PtdIns kinase activities? Such a description requires an understanding of how PtdIns kinases register substrate lipids. In vitro PtdIns kinase assays commonly present PtdIns to the kinase in the context of mixed phospholipid-detergent micelles. Although such presentation schemes support kinase activity, it is remarkable how poorly these enzymes register PtdIns residing in membrane bilayers [25]. One factor that no

Heterotypic phospholipid exchange and stimulation of PtdIns-kinases

The ability of a primed Sec14-like PITP (i.e. one associated with sensor ligand; such as PtdCho in the case of Sec14p) to switch into substrate-presentation mode via heterotypic exchange reactions raises interesting questions. These data suggest that primed Sec14-like PITPs generate a temporally and spatially regulated flurry of ‘presented’ PtdIns headgroups now susceptible to modification by PtdIns 4-OH kinases (Figure 5). The window of opportunity for a PtdIns kinase to modify the ‘presented’

Definition of sensing territories

Spatial and temporal restriction of PITP activity can be achieved by multiple paths. Protein–protein or protein–lipid interactions that involve the Sec14-like PITP surface (as opposed to the hydrophobic binding pocket) can restrict localization to membrane subdomains. Indeed, several yeast Sec14-like PITPs stably target specific intracellular locations 55, 95. The identities of proteins (or lipids) that impart specific localization to PITPs have yet to be described. PITP receptors are of

Concluding remarks

Recent progress, from various lines of research, is providing unprecedented insights into mechanisms for how lipid metabolism is incorporated into the engineering diagram for membrane trafficking and signaling. Realizations that Sec14-like PITPs integrate diverse aspects of lipid metabolism with PIP signaling, and the recent developments that contribute to a physical appreciation of how such integration could work, introduce several new questions for experimental address. Although we highlight

Acknowledgements

We thank Fred Maxfield, Anant Menon, Todd Graham, Chris Burd, Will Prinz, Pete Downes, Minoru Nakano and Eric Ortlund for useful discussions regarding the issues highlighted in this review. This work was supported by grants from the National Institutes of Health (to V.A.B.). G.S. is supported by grants from the Deutsche Forschungsgemeinschaft.

Glossary

ARF (ADP-ribosylation factor): a group of highly conserved GTPases of the Ras superfamily originally identified as cofactors in the cholera toxin-stimulated ADP ribosylation of G_s subunits of heterotrimeric G-proteins. ARFs are master regulators of membrane trafficking and do so in part by mediating the recruitment of proteins that form vesicle coats.
BCH (BNIP-2 and Cdc42GAP homology) domain: an approximately 145 amino acid domain first found in BNIP-2 and Cdc42GAP, also known as p50-RhoGAP, which

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Trends in Biochemical Sciences

ReviewThe Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling

Section snippets

Lipids and pathways for membrane trafficking

Lipid platforms

Lipid transfer proteins: in vitro veritas?

The Sec14p tale as told by cells

The Sec14 superfamily

Ligand binding by Sec14-like proteins

Coincidence sensors that couple lipid metabolic inputs to PIP synthesis

Instructive mechanisms for regulating PtdIns-kinase activity

Heterotypic phospholipid exchange and stimulation of PtdIns-kinases

Definition of sensing territories

Concluding remarks

Acknowledgements

Glossary

Cell

Trends Cell Biol.

Cell

Cell

Cell

Molecular Cell

J. Biol. Chem.

Biochim. Biophys. Acta

FEBS Lett.

Biochim. Biophys Acta.

Mol. Cell

J. Biol. Chem.

Curr. Biol.

J. Biol. Chem.

Biochem. Biophys. Res. Comm.

J. Biol. Chem.

Cell

J. Mol. Biol.

J. Mol. Biol.

J Mol Biol.

Biophys. J.

Biochim. Biophys. Acta

J. Biol. Chem.

Structure

The protein machinery of vesicle budding and fusion

Pro. Science

Coat proteins and vesicle budding

Science

Evidence that the inositol phospholipids are necessary for exocytosis: loss of inositol phospholipids and inhibition of secretion in permeabilized cells caused by bacterial phospholipase C and removal of ATP

Biochem. J.

An essential role for a phospholipid transfer protein in yeast Golgi function

Nature

A phosphatidylinositol transfer protein controls the phosphatidylcholine content of yeast Golgi membranes

J. Cell Biol.

Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca2+-activated secretion

Nature

ATP-dependent inositide phosphorylation required for Ca(2+)-activated secretion

Nature

Phospholipase D is present on Golgi-enriched membranes and its activation by ADP ribosylation factor is sensitive to brefeldin A

Proc. Natl. Acad. Sci. U.S.A.

Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting

Science

A protein's final ESCRT

Traffic

The yeast phosphatidylinositol-4-OH kinase Pik1 regulates secretion at the Golgi

Nature Cell Biol.

Direct involvement of phosphatidylinositol-4-phosphate in secretion in the yeast Saccharomyces cerevisiae

J. Biol. Chem.

Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function

J. Cell Biol.

SAC1p is an integral membrane protein that influences the cellular requirement for phospholipid transfer protein function and inositol in yeast

J Cell Biol.

SAC1-like domains of yeast SAC1, INP52 and INP53, and human synaptojanin encode polyphosphoinositide phosphatases

J. Biol. Chem.

Relationship between altered phospholipid metabolism, DAG, ‘bypass Sec14p’, and the inositol auxotrophy of yeast sac1 mutants

Mol. Biol. Cell

Kes1p shares homology with human oxysterol binding protein and participates in a novel regulatory pathway for yeast Golgi-derived transport vesicle biogenesis

EMBO J.

Analysis of oxysterol binding protein homologue Kes1p function in regulation of Sec14p-dependent protein transport from the yeast Golgi complex

J Cell Biol.

The oxysterol binding protein Kes1p regulates Golgi apparatus phosphatidylinositol-4-phosphate function

Proc. Natl. Acad. Sci. U. S. A.

Phosphatidylinositol 4,5-bisphosphate regulates SNARE-dependent membrane fusion

J. Cell Biol.

Review
The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling

Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca²⁺-activated secretion