Interactome Analysis of Human Phospholipase D and Phosphatidic Acid-Associated Protein Network

Han Han,Stephanie Pham,Rebecca Elizabeth Kattan,Gayoung Seo,Bing Yang,Yongqi Lin,Max Dotson,Yahya Menely,Wenqi Wang

doi:10.1016/j.mcpro.2022.100195

Han Han, Stephanie Pham + Show 7 more

Open Access

https://doi.org/10.1016/j.mcpro.2022.100195

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Abstract

Mammalian phospholipase D (PLD) enzyme family consists of six members. Among them, PLD1/2/6 catalyzes phosphatidic acid (PA) production, while PLD3/4/5 has no catalytic activities. Deregulation of the PLD-PA lipid signaling has been associated with various human diseases including cancer. However, a comprehensive analysis of the regulators and effectors for this crucial lipid metabolic pathway has not been fully achieved. Using a proteomic approach, we defined the protein interaction network for the human PLD family of enzymes and PA and revealed diverse cellular signaling events involving them. Through it, we identified PJA2 as a novel E3 ubiquitin ligase for PLD1 involved in control of the PLD1-mediated mammalian target of rapamycin signaling. Additionally, we showed that PA interacted with and positively regulated sphingosine kinase 1. Taken together, our study not only generates a rich interactome resource for further characterizing the human PLD-PA lipid signaling but also connects this important metabolic pathway with numerous biological processes.

Highlights

The phospholipase D (PLD) enzyme family is known for its catalytic action to produce phosphatidic acid (PA) [1]
In this study, we defined the protein interaction landscape for the human PLD family enzymes and their lipid product PA, and identified over 300 high-confident interacting protein (HCIP) for them, which greatly expanded our knowledge of this lipid metabolic pathway in diverse signaling events and cellular functions
PLD3 and PLD4 formed a complex with lysosome proteins TM9SFs (Figures 4A and 4E-4H), and overexpression of PLD3 induced the contact formation between endoplasmic reticulum (ER) and lysosomes (Figures 4I and 4J)

Summary

Introduction

The PLD enzyme family is known for its catalytic action to produce phosphatidic acid (PA) [1]. Among the human PLD enzymes, PLD1 and PLD2 are ubiquitously expressed in multiple tissues and play vital roles in various physiological processes, including receptormediated endocytosis, cell migration, cytoskeletal organization [6, 7]. Deregulation of these two PLD members have been associated with different human diseases [8, 9]. Our interactome analysis of the PLDs and PA-associated protein interaction network provides a rich resource for further exploration of this key lipid metabolic pathway in various signaling events and biological processes

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