Extracellular transglutaminase-2 in tissue fibrosis: a new therapeutic avenue

Extracellular transglutaminase-2 in tissue fibrosis: a new therapeutic avenue

TG2 has been implicated in the pathogenesis of many apparently unrelated diseases such as tissue fibrosis, celiac disease, cancers, neurodegenerative disorders, and type-2 diabetes. Although capable of different biological activities, overall its expression and activation is believed to occur as a response to tissue injury and / or cell stress. Protein cross-linking is the enzymatic reaction for which TG2 is better known, involving an acyl transfer reaction between the gamma carboxamide group of a peptide-bound Gln residue and the epsilon-amino group of a peptide-bound Lys residue or a primary amino group of a polyamine. TG2 causes additional post-translational modifications among which protein deamidation of Gln residues contributes to the development of disorders caused by gluten sensitivity. A recent review from our lab: Savoca et al 2018

What have we achieved?

  • Identification of a novel pathway mediated by TG2 via MUC1, contributing  to androgen insensitivity and malignancy in prostate cancer Silencing of TG2 by CRISPR-Cas9 is associated with upregulation of androgen receptor transcription in PCa cell lines and a reduced level of mucin-1 (MUC1), which was restored by selective add-back of the truncated TG2 isoform (TGM2_v2).  TG2 affects transcriptional regulation of MUC1 via repressing AR expression (Atobatele 2023)

  • Mapping of the TG2 interactome in chronic kidney disease (CKD). A differential proteomic approach was developed to identify disease gene-associated proteins in kidney membrane, with support from Kidney Research UK (study published in Furini et al 2018)

  • Identification of the role of Syndecan-4 in the biological activity of extracellular TG2 in fibrosis. The partnership of TG2 and Syndecan-4 was elucidated in experimental models of kidney fibrosis (unilateral ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN)) in vivo (Scarpellini et al 2014) and ex vivo  (Burhan et al 2016) 

  • Characterisation of the heparin binding property of TG2. The affinity binding of TG2 for heparan sulphate (HS) was demonstrated biochemically by solid binding assays and co-immunoprecipitation, and by double immunofluorescent staining of fixed and stained primary cells. The significance of the syndecan-4/HS-TG2 association in TG2 cell surface trafficking/localisation was investigated in primary cell models Scarpellini et al 2029; Lortat-Jacob&Burhan 2012; Furini 2019 

  • Identification of a TG2-fibronectin mediated cell survival pathway. A matrix TG2-mediated cell survival pathway independent of the Arg-Gly-Asp (RGD)-main cell adhesion site of fibronectin was reported with relevance in matrix fragmentation / tissue injury Telci 2008; Verderio 2003