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Phosphoinositides as membrane organizers

Nature Reviews Molecular Cell Biology volume 23, pages 797–816 (2022)Cite this article

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Abstract

Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially discovered for their roles in cell signalling, phosphoinositides are now widely recognized as key integrators of membrane dynamics that broadly impact on all aspects of cell physiology and on disease. The past decade has witnessed a vast expansion of our knowledge of phosphoinositide biology. On the endocytic and exocytic routes, phosphoinositides direct the inward and outward flow of membrane as vesicular traffic is coupled to the conversion of phosphoinositides. Moreover, recent findings on the roles of phosphoinositides in autophagy and the endolysosomal system challenge our view of lysosome biology. The non-vesicular exchange of lipids, ions and metabolites at membrane contact sites in between organelles has also been found to depend on phosphoinositides. Here we review our current understanding of how phosphoinositides shape and direct membrane dynamics to impact on cell physiology, and provide an overview of emerging concepts in phosphoinositide regulation.

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Fig. 1: Metabolism and subcellular enrichment of phosphoinositides.
Fig. 2: Phosphoinositide conversions during endocytosis and endosomal sorting.
Fig. 3: Phosphoinositide control of lysosome function.
Fig. 4: Phosphoinositides at membrane contact sites.

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Acknowledgements

The authors gratefully acknowledge support of their own work by grants from the Deutsche Forschungsgemeinschaft (TRR186/A08, HA2686/15-1 and HA2686/22-1 to V.H.), the European Union (H2020-MSCA-ITN-2015:675392 to V.H.), the Leibniz Association (SAW K216/2016 to V.H.) and the European Research Council (ERC-AdG to V.H.). W.J. was supported by a Leibniz-German Academic Exchange Service (DAAD) Research Fellowship (57423756) and the Postdoctoral Fellowship Program (Nurturing Next-generation Researchers) of the National Research Foundation of Korea (2018R1A6A3A03010583).

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  1. Department of Molecular Pharmacology and Cell Biology, Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany

    York Posor, Wonyul Jang & Volker Haucke

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  1. York Posor
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  2. Wonyul Jang
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  3. Volker Haucke
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The authors contributed equally to all aspects of the article.

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Correspondence to Volker Haucke.

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Nature Reviews Molecular Cell Biology thanks Harald Stenmark and Maria Antonietta De Matteis for their contribution to the peer review of this work.

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Glossary

Endosomes

Membrane-bound compartments on the endocytic route that can be distinguished as early, late and recycling endosomes. Early endosomes act as sorting stations and are marked by RAB5 and phosphatidylinositol 3-phosphate. They can mature into RAB7-positive late endosomes (also called ‘multivesicular bodies’) by inward budding. Recycling endosomes are tubular in nature and recycle cargo to the cell surface.

PtdIns 3-kinase

(PI3K). A family of lipid kinases that phosphorylate the 3′ position of the inositol head group of phosphatidylinositol (PtdIns) lipids. Class I PI3Ks act in receptor signalling, whereas class II and class III PI3Ks primarily control intracellular membrane dynamics.

Click chemistry

A class of biocompatible organic reactions that rapidly and selectively react (‘click’) with each other under mild, aqueous conditions.

Autophagy

A stress-inducible catabolic process that involves the formation of double membrane-bounded autophagosomes that fuse with lysosomes to mediate catabolic turnover of proteins, organelles or pathogens.

Phospholipase C

(PLC). A group of hydrolytic enzymes that cleave phosphatidylinositol 4,5-bisphosphate into inositol 3,4,5-trisphosphate and diacylglycerol.

COPII

Coatomer complex II, a type of coat protein that promotes the formation of secretory vesicles or tubules from exit sites of the endoplasmic reticulum to effect cargo transport to the endoplasmic reticulum–Golgi intermediate compartment.

trans-Golgi network

(TGN). A highly dynamic series of interconnected tubules and vesicles at the trans face of the Golgi stack. The TGN functions in the sorting and processing of glycoproteins and glycolipids at the interface of the biosynthetic and endosomal pathways (for example, protein secretion and the sorting of lysosomal enzymes).

Clathrin adaptor proteins

A collective term for proteins/protein complexes that recruit clathrin — a triskelial scaffold protein comprising three heavy chains and three associated light chains — to membranes and aid polymerization, often via binding to phosphoinositide lipids (for example, adaptor complexes AP1 and AP2, and monomeric GGA1, GGA2 and GGA3).

DOPEY1–MON2 complex

A protein complex comprising the peripheral Golgi membrane proteins DOPEY1 and MON2, a relative of the SEC7 family of guanine-nucleotide exchange factors for ARF GTPases, proposed to act as a phosphatidylinositol 4-phosphate-dependent kinesin adaptor for membrane traffic at the trans-Golgi network.

14-3-3 protein

A family of conserved regulatory proteins expressed in all eukaryotic cells that can bind to functionally diverse, usually phosphorylated signalling proteins to regulate their function.

Glycosphingolipids

A subclass of glycolipids that contain the amino alcohol sphingosine. They are found in the cell membranes of organisms from bacteria to humans and are the major glycolipids of animals.

Sphingomyelin

An abundant phosphosphingolipid in animal cell membranes; it is especially enriched in the membranous myelin sheath that surrounds some nerve cell axons. Its hydrolysis releases ceramide and phosphocholine.

Ceramide

Synthesized in the endoplasmic reticulum, the precursor of sphingomyelin. Glucosylceramide is the precursor of glycosphingolipids and is synthesized in the cis-Golgi network.

Schwann cells

The principal glia of the peripheral nervous system that function to support neurons by forming a myelin sheath around axons for insulation. Schwann cells are also important for nerve regeneration.

Synaptotagmin 1

A major type I transmembrane protein enriched in synaptic vesicles that acts as a calcium sensor for regulated exocytosis in central nervous system neurons.

Clathrin-mediated endocytosis

(CME). The internalization of plasma membrane and receptors present therein into small vesicles that is mediated by a protein coat containing clathrin, adaptors and accessory proteins. During endocytosis clathrin triskelia polymerize into hexagons and pentagons to promote endocytic vesicle formation.

Phox homology (PX) domain

A structurally conserved phosphoinositide-binding domain consisting of approximately 120 amino acids found in a wide range of proteins.

Dynamin

A large mechanochemical GTPase that oligomerizes at the neck of endocytic vesicles or tubules to promote membrane fission.

Pleckstrin homology (PH) domain

Sequence of approximately 100 amino acids that can mediate specific binding to phosphoinositide lipids and that is present in many signalling molecules. Only a minority of PH domains actually bind lipids, with the PH domain representing a conserved structural fold in proteins without necessarily a specific biological function.

Macropinocytosis

An evolutionarily conserved endocytic pathway that allows internalization of extracellular fluid via large endocytic vesicles called ‘macropinosomes’.

Nucleation-promoting factors

Factors such as WASP, N-WASP and Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) that stimulate the intrinsically low activity of the ARP2/3 complex to nucleate actin filaments.

ARP2/3 complex

Actin-related protein 2/3 complex, a seven-subunit protein complex that acts to promote the nucleation of branched actin filaments in eukaryotic cells.

CLIC–GEEC pathway

A major clathrin-independent pinocytic pathway mediated by uncoated tubulovesicular carriers called ‘clathrin-independent carriers’ (CLICs) that mature into tubular early endocytic compartments called ‘glycosylphosphatidylinositol-anchored protein enriched compartments’ (GEECs).

Multivesicular bodies

An alternative term for RAB7-positive late endosomes that form by inward budding of vesicles into the endosome lumen.

Retromer

An evolutionarily conserved heterotetrameric complex involved in recycling of cargo from endosomes. It is composed of a membrane-associated sorting nexin (SNX3 or SNX27), and a vacuolar protein sorting trimer containing VPS26, VPS29 and VPS35.

Retriever

Structurally and functionally related to retromer, the retriever complex comprises sorting nexin 17 (SNX17) and the CCC complex.

ESCPE-1

Endosomal sorting nexin (SNX)–Bin–Amphiphysin–Rvs (BAR) sorting complex for promoting exit 1, a heterodimer of either SNX5 or SNX6 with either SNX1 or SNX2 that mediates retrieval of a subset of cargoes independently of retromer.

Charcot–Marie–Tooth disease

A group of hereditary motor and sensory neuropathies that damage the peripheral nerves. Charcot–Marie–Tooth disease type 4B is a rare subtype of the disease caused by mutations in the phosphoinositide 3-phosphatase myotubularin-related protein 2 (MTMR2).

Primary cilia

Non-motile type of cilia comprising an axoneme of nine doublet microtubules that are found on nearly all eukaryotic cells and function as microscopic sensory antennae.

X-linked centronuclear myopathy

A severe human disease characterized by muscle fibre defects that result from mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin 1 (MTM1).

FYVE domain

A phosphatidylinositol 3-phosphate-binding domain of approximately 60–65 amino acids that is named after the four cysteine-rich proteins FAB1, YOTB, VAC1 and EEA1, in which it has been found.

PIKfyve

An evolutionarily conserved complex comprising the lipid kinase PIKfyve, the scaffold protein VAC14, and the putative 5-phosphatase FIG4. It mediates synthesis of lysosomal phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate in eukaryotic cells.

Mechanistic target of rapamycin complex 1

(mTORC1). A multiprotein assembly composed of the kinase mTOR, a distant relative of the phosphatidylinositol 3-kinases, regulatory associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and DEP domain-containing mTOR-interacting protein (DEPTOR) that promotes anabolism.

PROPPIN domain

β-Propeller that binds polyphosphoinositides, a domain containing WD40 motifs and that has been identified in autophagy proteins such as yeast Atg18 and mammalian WD repeat domain phosphoinositide-interacting proteins (WIPI proteins). Via its β-propeller fold, it binds bind to phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate.

LC3 family proteins

Proteins comprising microtubule-associated protein 1A/1B light chain 3 (LC3) and the closely related GABARAP proteins; they share structural homology with ubiquitin. They play key roles in autophagy.

Cortactin

An actin nucleation-promoting factor that binds to F-actin filaments and to the ARP2/3 complex to regulate cell shape and movement.

Joubert syndrome

A rare autosomal recessive disorder that is characterized by a distinctive cerebellar and brainstem malformation resulting in ataxia, mental retardation and retina degeneration. Among the genetic causes of the disease are loss-of-function mutations in the phosphoinositide 5-phosphatase INPP5E.

Familial cerebellar atrophy

Cerebellar degeneration caused by inherited gene changes.

Vacuolar ATPase

An ATP-driven proton pump that is closely related to the mitochondrial FoF1-ATPases and that is responsible for the lumenal acidification of endosomes, lysosomes and related organelles.

RAG small GTPases

A unique family of evolutionarily conserved, heterodimeric, lysosome-localized small GTPases that promote anabolic processes through activation of mechanistic target of rapamycin complex 1 signalling in the presence of abundant amino acids.

Hereditary spastic paraplegia

A group of rare inherited disorders that cause weakness and stiffness in the leg muscles.

C2 domains

A membrane-binding domain homologous to the C2 domain of protein kinase C with mostly only moderate lipid specificity. Some C2 domains associate with membranes in a Ca2+-dependent manner.

Store-operated Ca2+ entry

The regulated entry of Ca2+ into cells in response to the depletion of Ca2+ in the endoplasmic reticulum.

FFAT motif

A peptide sequence (with, for example, two phenylalanines in an acidic tract) that binds to VAMP-associated proteins (VAPs) to facilitate the formation of endoplasmic reticulum-based membrane contact sites.

Focal adhesion kinase

(FAK). A cytoplasmic non-receptor tyrosine kinase that localizes to focal adhesions and contributes to integrin-mediated cell signalling.

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Posor, Y., Jang, W. & Haucke, V. Phosphoinositides as membrane organizers. Nat Rev Mol Cell Biol 23, 797–816 (2022). https://doi.org/10.1038/s41580-022-00490-x

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