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

Abstract

Background: 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. 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. Results: In 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. Conclusions: This study describes TMIGD1 as an adhesion receptor that can localize to both mitochondria and cellcell 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.

Genome-Wide Association Study of Motor Coordination

“…The most significantly associated SNP fell within a 60Kb region within 14q24.2, overlapping with the 5’ region SYNJ2BP , the 3’ end of ADAM20 , and the entirety of ADAM21 . SYNJ2BP, synaptojanin 2 binding protein (OMIM ∗ 609411) is located on the outer membrane of the mitochondria ( Hartmann et al, 2020 ) and forms an unusual gene read-through product with neighboring gene COX16 (OMIM ∗ 618064) ( Figure 4 ), a known mitochondrial complex IV assembly factor ( Cerqua et al, 2018 ). Mitochondria play a vital role in brain function, and therefore this represents an interesting potential mechanism to further explore.…”

A novel adhesive complex at the base of intestinal microvilli

“…TMIGD1 is predominantly expressed by epithelial cells of the kidney (Arafa et al , 2015; Hartmann et al , 2020) and of the small intestine (Cattaneo et al , 2011; Zabana et al , 2020). In two colon-derived cell lines, i.e.…”

“…TMIGD1 constructs in pInducer21-Puro: hTMIGD1 full length (AA1-262).TMIGD1 constructs in pcDNA3 (Invitrogen): hTMIGD1 full length (AA1-262), hTMIGD1 lacking the PDZ domain binding motif (hTMIGD1/Δ5, AA 1-258), hTMIGD1 lacking the cytoplasmic domain (hTMIGD1/ΔCP, AA 1-241). Flag-tagged TMIGD1-EGFP constructs in pKE1079(Hartmann et al, 2020): EGFP-hTMIGD1 (AA 30-262, EGFP inserted between AA211 and AA212 of TMIGD1); EGFP-TMIGD1-JAM-A (NH 2 -TMIGD1-30-211-EGFP-JAM-A-231-299-COOH). GST-tagged TMIGD1 constructs in pGEX-4T-1 (GE Healthcare): GST-TMIGD1 (hTMIGD1 cytoplasmic tail (AA 242-262); GST-TMIGD1/Δ5: hTMIGD1 cytoplasmic tail lacking the PDZ domain binding motif (AA 242-257).…”

Structure and Function of Mitochondria‐Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases

“…BAP31 is also involved in the attenuated sepsis-mediated myocardial depression by melatonin [42]. Recent data have suggested that synaptojanin-2binding protein (SYNJ2BP) localized on the OMM interacts with ribosome-binding protein 1 (RRBP1), and once SYNJ2BP is overexpressed, the mitochondria-ER contacts dramatically increase [44].…”