Spotlight on the Transglutaminase 2-Heparan Sulfate Interaction

Abstract

Heparan sulfate proteoglycans (HSPGs), syndecan-4 (Sdc4) especially, have been suggested as potential partners of transglutaminase-2 (TG2) in kidney and cardiac fibrosis, metastatic cancer, neurodegeneration and coeliac disease. The proposed role for HSPGs in the trafficking of TG2 at the cell surface and in the extracellular matrix (ECM) has been linked to the fibrogenic action of TG2 in experimental models of kidney fibrosis. As the TG2-HSPG interaction is largely mediated by the heparan sulfate (HS) chains of proteoglycans, in the past few years a number of studies have investigated the affinity of TG2 for HS, and the TG2 heparin binding site has been mapped with alternative outlooks. In this review, we aim to provide a compendium of the main literature available on the interaction of TG2 with HS, with reference to the pathological processes in which extracellular TG2 plays a role.

The Transglutaminase-2 Interactome in the APP23 Mouse Model of Alzheimer’s Disease

“…In AD, Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses, suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks, resulting in neurodegeneration [51]. TG2 is also closely linked to the cell adhesion process, in which it interacts with an array of matrix molecules such as integrin, growth factor receptors, and other cell surface or extracellular matrix proteins, in particular fibronectin and heparan sulfate proteoglycans, to trigger adhesion signaling [52][53][54]. Modifications in the synaptic vesicle-related pathways are also well known for AD, as results of human and animal AD model studies demonstrate considerable changes in the expression and functions of presynaptic proteins, attributed in part to direct effects of Aβ on the synaptic vesicle cycle (SVC) [55].…”

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease

“…However, no information is actually available about a link between P31-43 and proteoglycans. Interestingly, heparan sulphate proteoglycans, in particular syndecan-4, are cell surface interactors of TG2, potentially modulating its pathophysiological functions [80].…”

Insights into the heparan sulphate-dependent externalisation of transglutaminase-2 (TG2) in glucose-stimulated proximal-like tubular epithelial cells

“…To test whether the interaction of HS with the heparin binding site of TG2 is responsible for its cell surface location, NRK-52E cells were transiently transfected with previously characterised TG2 heparin binding mutants [27], and the level of cell surface TG2 measured. Mutant cDNAs were selected based on enzymatic activity and thermal shift analysis described in our previous work [27], as they expressed mutant TG2s with similar enzymatic activity and stability to the WT enzyme; moreover, they could be modulated by Ca 2+ and GTP like the wild type enzyme [27,30]. Mutant M1c disrupted the 261-LRRWK-265 sequence while M3 the 598-KQKRK-602 TG2 sequence of TG2.…”

“…Recently, the presence of clusters of exosomal proteins in the TG2-membrane interactome has led to the demonstration that TG2 can be externalised via extracellular membrane vesicles by TEC during CKD progression, in a way which is dependent on the heparan sulphate (HS) proteoglycan syndecan-4 [22]. TG2 affinity for the HS chains has led to the mapping of the TG2 heparin binding site, showing that heparin binding is lost when TG2 is in the linear ("active") conformation [27][28][29] [recently reviewed in [30]]. Vesicular secretion of TG2 has been proposed also in other cell systems [31], and the N-ethylmaleimide (NEM), inhibitor of membrane fusion of NSF ATPase, has been shown to interfere with TG2 secretion in NIH/3T3 [31].…”