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.
Highlights
We previously identified two TG2 variants, along with the canonical TG2, in the rat SNx experimental model of chronic kidney disease and reported that these increase in expression post-SNx [63]
The affinity of TG2 for the heparan sulfate (HS) chains of Heparan sulfate proteoglycans (HSPGs), Sdc4 in particular, has only started to be characterised, as not much is known on the nature of the HS structure and the degree of sulfation required for TG2 binding
We know that Sdc4 plays an emerging role in the cell surface trafficking and extracellular activity of TG2, being implicated in the externalisation pathway of TG2 either by trapping
Summary
Transglutaminase-2 (TG2) is the most ubiquitous isoenzyme of the transglutaminase (TG) family, present in virtually all tissues and cell types and involved in a large spectrum of biological functions [1,2,3]. TG2 was originally described as a cytosolic protein, we know that TG2 is located at the cell surface and extracellular space of many cell types, where it promotes stabilisation and deposition of the extracellular matrix (ECM) via its calcium-dependent crosslinking activity [27,28,29,30]. TG2 has a further non-enzymatic role, acting as a structural protein in complex with fibronectin (FN) and interacting with integrins and heparan sulfate proteoglycans (HSPGs) to promote cell adhesion and spreading [30,31,32,33,34,35,36]. The non-enzymatic activity of TG2 as a scaffold protein promotes cell adhesion and migration, especially in the context of matrix fragmentation/cell injury [32,33,34]. We will describe the main characteristics and biological roles of HSPGs and comprehensively review the literature that has investigated the interaction between HSPGs and TG2 in the past 15 years
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