Novel roles of phosphoinositides in signaling, lipid transport, and disease

doi:10.1016/j.ceb.2019.12.007

Current Opinion in Cell Biology

Volume 63, April 2020, Pages 57-67

https://doi.org/10.1016/j.ceb.2019.12.007 Get rights and content

Abstract

Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad cellular processes and multiple human diseases mediated by misregulation of PPIn signaling. This review will present a timely summary of recent discoveries in PPIn biology, specifically their role in regulating unexpected signaling pathways, modification of signaling outcomes downstream of integral membrane proteins, and novel roles in lipid transport. This has revealed new roles of PPIns in regulating membrane trafficking, immunity, cell polarity, and response to extracellular signals. A specific focus will be on novel opportunities to target PPIn metabolism for treatment of human diseases, including cancer, pathogen infection, developmental disorders, and immune disorders.

Introduction

Phosphoinositides (PPIns) are lipid signaling molecules that coordinate numerous aspects of membrane trafficking and cell signaling in eukaryotic cells. Their action is essential in cell growth, metabolism, and cell death [1]. The enzymes that modify PPIns (kinases, phosphatases, and lipases) are critically linked to multiple human diseases, with mutations leading to cancer, immune disorders, developmental disorders, and inflammatory diseases [∗2, 3, 4]. There are 7 different PPIn species (Figure 1a), with all of them acting as regulators of temporal and spatial signaling events (Figure 1b). The canonical view of PPIn signaling has focused on their role in both the recruitment (Figure 2a) and allosteric activation of proteins at specific intracellular locations (Figure 2b). PPIn-mediated recruitment of proteins to specific organelles can mark their final destination in membrane trafficking [5], modify biophysical properties of membranes [6], and provide spatial regulation of signaling.

However, recent years have seen an explosion in our understanding of other key roles of PPIns, including their role in modulating integral membrane protein signaling (Figure 2c), and regulating lipid transport (Figure 2d). This review will highlight recent discoveries in PPIn biology, focusing on four specific areas: novel roles of PPIns in signaling, PPIn regulation of integral membrane proteins, how PPIns and lipid transfer proteins mediate lipid exchange against thermodynamic gradients, and finally novel discoveries toward treating human disease by targeting PPIn-metabolizing enzymes. For more comprehensive coverage of PPIn function in, for example, cytoskeletal dynamics and nuclear function, we refer the reader to several recent, comprehensive reviews [7,8].

Section snippets

Noncanonical roles of PPIns in recruitment of cellular signaling machinery

The canonical view of PPIn signaling is the recruitment of specific lipid-binding domains to intracellular membranes, with multiple domains putatively identified as specific PPIn binders (PX, PH, FYVE, etc., for an in-depth review readers are advised to consult [9,10]). The recruitment of these domains to specific intracellular organelles can mediate signaling not only through localization but also through lipid binding–mediated conformational changes [11, 12, 13]. Exhaustive analysis of these

PPIns as regulators of integral membrane protein signaling

The binding of PPIns to integral membrane proteins can modulate their activity and can allow for activation of integral membrane proteins to only occur when they are in specific membrane organelles. PPIns can regulate integral membrane proteins through multiple mechanisms: they can induce allosteric conformational changes and/or mediate coupling to protein binding partners. PPIns have long been known to be key regulators of ion channels, with PI(4,5)P₂ identified as a key regulator of channel

PPIns and lipid transfer proteins

Evidence is emerging that lipid transfer proteins (LTPs) can use PPIns in a novel way (Figure 4): as a means to couple the energy of ATP hydrolysis to the transport of lipid cargoes against a concentration gradient at membrane contact sites (MCSs). So far, evidence implicates this mechanism for enrichment of trans-Golgi network (TGN) cholesterol and PM phosphatidylserine (PS) [52,53]. In both cases, members of the oxysterol binding protein–related protein (ORP) family and the PPIn PI4P are

Novel insight into targeting pathological PPIn metabolism in disease

The most clinically advanced strategy targeting pathologies in PPIn signaling has been targeting the PI3K pathway in cancer, immunodeficiencies, and growth disorders. Currently there are four clinically approved PI3K inhibitors [2,∗70, 71, 72, 73]; however, there has been little success in targeting solid tumors with this approach, with various deleterious side effects. Recent discoveries suggest there may be unique additional opportunities to target this pathway in disease. Inhibitors specific

Conclusions and future directions

PPIns are master regulators of signaling in almost every intracellular membrane compartment. The development of novel tools to interrogate PPIn metabolism have revealed exciting new insight into their roles in controlling membrane trafficking, metabolism, autophagy, and signaling. The classical understanding of PPIn signaling was as messengers that could recruit and/or activate soluble effector proteins. As we have seen, our knowledge of the repertoire of such proteins and their associated

Author contributions

JEB and GRVH equally split all writing, including conceptualization, drafting, editing, and generation of figures.

Conflict of interest statement

Nothing declared.

Acknowledgements

Work in the Burke Laboratory is supported by research grants from Canadian Institute of Helath Research (CRN-142393), Natural Science and Engineering Research Council of Canada (Discovery grant 2014-05218), and the Cancer Research Society (CRS 24368) along with salary awards from CIHR (New investigator award) and the Michael Smith Foundation for Health Research (Scholar 17686). Work in the Hammond Laboratory is supported by National Institutes of Health grant 1R35GM119412-01.

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Novel roles of phosphoinositides in signaling, lipid transport, and disease

Abstract

Introduction

Section snippets

Noncanonical roles of PPIns in recruitment of cellular signaling machinery

PPIns as regulators of integral membrane protein signaling

PPIns and lipid transfer proteins

Novel insight into targeting pathological PPIn metabolism in disease

Conclusions and future directions

Author contributions

Conflict of interest statement

Acknowledgements

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