G-protein coupling and nuclear translocation of the human abscisic acid receptor LANCL2.

Chiara Fresia,Valeria Booz,Cesare Usai,Laura Sturla,Tiziana Vigliarolo,Mattia Pesce,Lucrezia Guida,Antonio De Flora,Elena Zocchi,Melody Di Bona,Santina Bruzzone

doi:10.1038/srep26658

Chiara Fresia, Valeria Booz + Show 9 more

Open Access

https://doi.org/10.1038/srep26658

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Abstract

Abscisic acid (ABA), a long known phytohormone, has been recently demonstrated to be present also in humans, where it targets cells of the innate immune response, mesenchymal and hemopoietic stem cells and cells involved in the regulation of systemic glucose homeostasis. LANCL2, a peripheral membrane protein, is the mammalian ABA receptor. We show that N-terminal glycine myristoylation causes LANCL2 localization to the plasmamembrane and to cytoplasmic membrane vesicles, where it interacts with the α subunit of a Gi protein and starts the ABA signaling pathway via activation of adenylate cyclase. Demyristoylation of LANCL2 by chemical or genetic means triggers its nuclear translocation. Nuclear enrichment of native LANCL2 is also induced by ABA treatment. Therefore human LANCL2 is a non-transmembrane G protein-coupled receptor susceptible to hormone-induced nuclear translocation.

Highlights

LANCL2-mediated abscisic acid (ABA) signaling in mammals requires a pertussis toxin (PTX)-sensitive G protein[5], eventually leading to an increase of intracellular Ca2+ levels ([Ca2+]i)
We demonstrated that N-terminal glycine myristoylation causes LANCL2 localization to the plasmamembrane and to cytoplasmic membrane vesicles as well
Evidence has recently been provided of non-canonical subcellular sites for G protein activation: these include endosomal localization of functionally active GPCR39–41, and the interaction of the GIV/Girdin protein, a non-receptor guanine nucleotide exchange factor, with heterotrimeric G proteins at the Golgi[42,43] and at still undefined intracellular sites[44]

Summary

Introduction

LANCL2-mediated ABA signaling in mammals requires a pertussis toxin (PTX)-sensitive G protein[5], eventually leading to an increase of intracellular Ca2+ levels ([Ca2+]i). The signaling pathway downstream of ABA binding to LANCL2 involves the activation of adenylate cyclase (AC), followed by overproduction of cAMP, PKA-catalyzed phosphorylation and stimulation of the plasmamembrane-bound ADP-ribosyl cyclase CD38, which converts NAD+ to cADPR and ADPR, leading to an increase of both extracellular Ca2+ entry and Calcium-induced calcium release (CICR)-mediated intracellular Ca2+ mobilization[5,9,15,21]. The non-myristoylated LANCL2-GFP fusion protein has been found to be confined to the nucleus[28]. This observation raises the possibility that its hormone ligand ABA may affect the trafficking of LANCL2 between membranes and nucleus. Recent findings allow to reconcile the non-transmembrane localization of LANCL2 with its hormone receptor function, as the human anion exchanger AE1 has been shown to mediate ABA transport across the plasmamembrane[30]

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