The mitochondrial outer membrane protein SYNJ2BP interacts with the cell adhesion molecule TMIGD1 and can recruit it to mitochondria

Christian Hartmann,Ysabel Alessa Schwietzer,Nils Kirschnick,Mark Glaesner-Ebnet,Stefan Reuter,Esther Hoppe,Daniel Kummer,Frauke Brinkmann,Masanori Nakayama,Eva-Maria Thüring,Klaus Ebnet,Volker Gerke

doi:10.1186/s12860-020-00274-1

Abstract

BackgroundTransmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is a recently identified cell adhesion molecule which is predominantly expressed by epithelial cells of the intestine and the kidney. Its expression is downregulated in both colon and renal cancer suggesting a tumor suppressive activity. The function of TMIGD1 at the cellular level is largely unclear. Published work suggests a protective role of TMIGD1 during oxidative stress in kidney epithelial cells, but the underlying molecular mechanisms are unknown.ResultsIn this study, we address the subcellular localization of TMIGD1 in renal epithelial cells and identify a cytoplasmic scaffold protein as interaction partner of TMIGD1. We find that TMIGD1 localizes to different compartments in renal epithelial cells and that this localization is regulated by cell confluency. Whereas it localizes to mitochondria in subconfluent cells it is localized at cell-cell contacts in confluent cells. We find that cell-cell contact localization is regulated by N-glycosylation and that both the extracellular and the cytoplasmic domain contribute to this localization. We identify Synaptojanin 2-binding protein (SYNJ2BP), a PDZ domain-containing cytoplasmic protein, which localizes to both mitochondria and the plasma membrane, as interaction partner of TMIGD1. The interaction of TMIGD1 and SYNJ2BP is mediated by the PDZ domain of SYNJ2BP and the C-terminal PDZ domain-binding motif of TMIGD1. We also find that SYNJ2BP can actively recruit TMIGD1 to mitochondria providing a potential mechanism for the localization of TMIGD1 at mitochondria.ConclusionsThis study describes TMIGD1 as an adhesion receptor that can localize to both mitochondria and cell-cell junctions in renal epithelial cells. It identifies SYNJ2BP as an interaction partner of TMIGD1 providing a potential mechanism underlying the localization of TMIGD1 at mitochondria. The study thus lays the basis for a better understanding of the molecular function of TMIGD1 during oxidative stress regulation.

Highlights

Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is a recently identified cell adhesion molecule which is predominantly expressed by epithelial cells of the intestine and the kidney
TMIGD1 is transported from the cytoplasm to the cell surface after deletion of the D1 Ig domain Given the high similarity of TMIGD1 to members of the Junctional Adhesion Molecule (JAM) family [6], and its predominant expression by kidney-derived epithelial cells [8, 14], we aimed to characterize the subcellular localization of TMIGD1 in kidney epithelial cells
Quantification of cell-cell contacts positive for ΔD1-TMIGD1 and ΔD1TMIGD1/Δ5 indicated that the number of ΔD1TMIGD1/Δ5-positive contacts was significantly lower than the number of ΔD1-TMIGD1-positive contacts (Fig. 1e), strongly suggesting that a PDZ domainmediated interaction is required for the stable localization of this construct at cell-cell junctions

Summary

Introduction

Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is a recently identified cell adhesion molecule which is predominantly expressed by epithelial cells of the intestine and the kidney. Epithelial cells and endothelial cells are connected by cell adhesion receptors localized at intercellular junctions. These adhesion receptors are required to mediate physical cell cohesion and to transmit signals and to mediate intercellular communication. The genes encoding cell adhesion receptors have been subjected to multiplication and diversification during evolution resulting in large families of cell-cell adhesion receptors, including the cadherin and the immunoglobulin superfamilies [1, 2]. The promiscuous nature of many of the motif - domain interactions has further contributed to the pleiotropic functions of cell-cell adhesion receptors [4, 5]

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