The N-terminal tail coordinates with carbohydrate recognition domain to mediate galectin-3 induced apoptosis in T cells

Abstract

Galectin-3 is a galectin with a unique flexible N-terminal tail (NT) connected to the conserved carbohydrate recognition domain (CRD). Galectin-3 is associated with tumor immune tolerance and exhibits an ability to induce T cell apoptosis. We used Jurkat, Jurkat E6-1 and CEM T-cell lines and human peripheral blood mononuclear cells (PBMCs) to investigate the specific roles of the CRD and NT in inducing T cell apoptosis. Galectin-3 triggered sustained extracellular signal-regulated kinase (ERK) phosphorylation that induced apoptosis. ERK was situated upstream of caspase-9 and was independently activated by reactive oxygen species (ROS) and protein kinase C (PKC). The first twelve NT residues had no role in the apoptosis. Residues 13-68 were essential for activating ROS, but did not activate PKC. However, residues 69-110 were required for activation of PKC. An NT fragment and a NT-specific antibody antagonized the apoptosis triggered by full-length galectin-3 further supporting our findings. These findings indicate the CRD and NT play important roles during induction of T cell apoptosis, which suggests their potential as therapeutic targets for reversing cancer immune tolerance.

The Role of Galectins as Modulators of Metabolism and Inflammation

“…Galectin-3 is the only chimera galectin; it has a C-terminal carbohydrate recognition domain as well as an N-terminal tail. Galectin-3 can, like galectin-1, induce T-cell apoptosis [ 33 ]; the N-terminal end and the CRD coordinate to induce signalling pathways leading to caspase-9 activation [ 34 ]. Inhibiting the N -terminal end with an antibody shuts down apoptosis stimulation [ 34 ].…”

A Synthetic Tetramer of Galectin-1 and Galectin-3 Amplifies Pro-apoptotic Signaling by Integrating the Activity of Both Galectins

“…The pathways through which extracellular G3 induces apoptosis are less understood at present. Early reports demonstrated that extracellular G3 signals apoptosis via cytochrome c-release and caspase-3 activation independent of caspase-8 activation (Fukumori et al, 2003), with more recent data suggesting that G3 activates caspase-9 upstream of caspase-3 through phosphorylation of extracellular signal-regulated kinase (ERK) (Xue et al, 2017).…”

CD146 interacts with galectin‐3 to mediate endothelial cell migration

“…It has been proposed that Gal‐3 can oligomerize via interactions of its NT . Although the NT coordinates with the CRD to initiate different apoptotic signaling pathways in T cells , the CRD is the main contributor of Gal‐3's lectin activity. Gal‐3 is involved in many physiological and pathological processes, including an induction of endothelial cell migration, tube formation, and sprouting, all of which are critical steps in angiogenesis .…”

“…It has been proposed that Gal-3 can oligomerize via interactions of its NT [16]. Although the NT coordinates with the CRD to initiate different apoptotic signaling pathways in T cells [17], the CRD is the main contributor of Gal-3's lectin activity. Gal-3 is involved in many physiological and pathological processes, including an induction of Abbreviations CD146 eFL, CD146 extracellular full length; CRD, carbohydrate-binding domain; DMEM, Dulbecco's modified Eagle's medium; Gal-3, Galectin-3; HMEC-1, human microvascular endothelial cell.…”