Review
PI(4,5)P2 regulation of surface membrane traffic

https://doi.org/10.1016/S0955-0674(00)00241-6Get rights and content

Abstract

Phosphatidylinositol 4,5-biphosphate (PI[4,5]P2) has emerged as an important signaling molecule in the membrane for regulating vesicle exo- and endocytosis and the accompanying actin cytoskeletal rearrangements. Localization studies with GFP-tagged binding domains and antibodies provide new views of the non-uniform, dynamic distribution of PI(4,5)P2 in membranes and its organization in raft-like domains. The targeting of phosphoinositide kinases by GTPases can coordinate the reactions of membrane fusion and fission with cytoskeletal assembly, providing a basis for membrane movement.

Introduction

In addition to its established role as a precursor for the signaling molecules Ins (1,4,5)P3 (inositol 1•, 4, 5 trisphosphate) and phosphatidylinositol (3,4,5) triphosphate (PI[3,4,5]P3) phosphatidylinositol (4,5)-biphosphate (PI[4,5]P2) is now recognized as an important plasma membrane signal that establishes sites for vesicular trafficking, membrane movement and actin cytoskeletal assembly. The signaling role of PI(4,5)P2 is mediated through interactions with proteins required for membrane trafficking and cytoskeleton assembly that contain PI(4,5)P2-binding domains. The pleckstrin homology (PH) domain is the best characterized of these, but many other novel Lys/Arg-rich PI(4,5)P2-binding domains have been identified. An important limitation for understanding the role of PI(4,5)P2 as a signal has been the difficulty of determining its distribution in the membrane. Dramatic recent progress in visualizing phosphoinositides has provided new information for correlating localized membrane PI(4,5)P2 levels with accompanying PI(4,5)P2-regulated events 1•, 2•.

PI(4,5)P2 on the plasma membrane, as well as on trafficking vesicles, is distributed non-uniformly and may be located in raft-like domains. PI(4,5)P2 at these sites coordinates membrane fission and fusion reactions with actin filament assembly to promote membrane movement. There is a new understanding of the targeting mechanisms that regulate the localized de novo synthesis of PI(4,5)P2 in the membrane. ARF proteins and other GTPases can coordinate membrane and cytoskeleton changes by utilizing phosphoinositide kinases as effectors. This article will highlight recent progress in localizing PI(4,5)P2, elucidating mechanisms for its localized synthesis and delineating its roles as a signal for coordinating membrane trafficking and cytoskeletal events Fig. 1.

Section snippets

Gradients and rafts of phosphatidylinositol 4,5-biphosphate

The appreciation that PI(4,5)P2 regulates spatially localized membrane events 3, 4, 5, 6 led to the suggestion that PI(4,5)P2 synthesis must be localized to specific membrane domains. Experimental methods to detect localized phosphoinositide pools and changes therein were limited before the introduction of GFP fusion protein chimeras that contain phosphoinositide-binding domains 1•, 2•. PH domains that detect PI(4,5)P2, PI(3,4,5)P3 or PI(3,4)P2 7, 8, 9, ENTH (epsin amino terminal homology)

GTPases mediate membrane recruitment of phosphoinositide kinases

Dynamic and localized de novo biogenesis of PI(4,5)P2 requires mechanisms that recruit phosphoinositide kinases to specific membrane domains. PI(4)P 5-kinases are recruited to active sites of cytoskeleton assembly at membrane ruffles 23••, to sites of phagosome formation 16• and to Golgi membranes 24••, 25•• where both membrane and cytoskeleton reorganization occurs. A major step toward understanding phosphoinositide kinase targeting is the finding that members of the ARF family of GTPases

Role for phosphatidylinositol 4,5-biphosphate in Golgi vesicle budding

The exit of protein cargo from the Golgi by the formation of transport vesicles in the trans-Golgi network (TGN) requires PI(4,5)P2. The yeast SEC14 gene encodes a PI transfer protein required for the formation of Golgi-derived secretory vesicles 36. Sec14p may be required for PI(4)P synthesis because levels of this phospho inositide are reduced in sec14 mutants but restored in sec14sac1 double mutants in which Golgi transport is restored 36, 37, 38, 39. Sac1p is a phosphatase that can

Role for phosphatidylinositol 4,5-biphosphate in vesicle fusion

In addition to vesicle budding, PI(4,5)P2 is essential for vesicle membrane fusion in a number of systems 4, but the precise role that PI(4,5)P2 plays is uncertain. Mechanistic studies of the role of PI(4,5)P2 in yeast vacuolar fusion in vitro revealed that PI(4,5)P2 operates at two distinct stages of the vacuolar fusion pathway 48. The first of these is at an ATP-dependent priming step during which NSF disassembles SNARE protein complexes prior to vacuole docking. PI(4,5)P2 is also required

Roles for phosphatidylinositol 4,5-biphosphate in vesicle fission and endocytosis

The coupling of surface membrane traffic to cytoskeletal regulation is exemplified by the process of endocytosis, and PI(4,5)P2 plays an essential role in this. Clathrin-mediated endocytosis requires an array of accessory proteins that function in coat assembly, membrane invagination, fission of the budded vesicle and vesicle uncoating. PI(4,5)P2 is essential at several stages of endocytosis for the sequential recruitment of adapter and accessory proteins to endocytic sites 51. Membrane

Phosphatidylinositol 4,5-biphosphate regulates vesicle motility

A concerted role for PI(4,5)P2 in regulating actin filament assembly and vesicular trafficking has become more evident with the characterization of an actin-based vesicle motility mechanism involving comet tail propulsion 58. A core of proteins in the Arp2/3 complex nucleates polymerization of new actin filaments to create a branching network with free fast-growing barbed filament ends oriented in the opposite direction to vesicle movement. Members of the WASP family of proteins were identified

Conclusions

The plasma membrane is a dynamic surface that undergoes shape changes in the form of protrusions and ruffles and content changes mediated by the insertion and uptake of membrane by exocytic and endocytic vesicular traffic. These processes occur in concert with, and may in some cases be driven by, remodeling of the subplasmalemmal actin cytoskeleton 65•. Recent work highlights the importance of PI(4,5)P2 as a signal that may coordinate membrane fission, fusion and movement with actin filament

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • •of special interest

  • ••of outstanding interest

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