Human tissue transglutaminase is inhibited by pharmacologic and chemical acetylation

Abstract

Human tissue transglutaminase (TGM2) is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's, Parkinson's and expanded polyglutamine (polyQ) diseases. TGM2 promotes formation of soluble and insoluble high molecular weight aggregates by catalyzing a covalent linkage between peptide-bound Q residues in polyQ proteins and a peptide-bound Lys residue. Therapeutic approaches to modulate the activity of TGM2 are needed to proceed with studies to test the efficacy of TGM2 inhibition in disease processes. We investigated whether acetylation of Lys-residues by sulfosuccinimidyl acetate (SNA) or aspirin (ASA) would alter the crosslinking activity of TGM2. Acetylation by either SNA and/or ASA resulted in a loss of >90% of crosslinking activity. The Lys residues that were critical for inhibition were identified by mass spectrometry as Lys . Hence, acetylation of Lys-residues may modulate the enzymatic function of TGM2 in vivo and offer a novel approach to treatment of TGM2 mediated disorders.

Conformational changes and translocation of tissue-transglutaminase to the plasma membranes: role in cancer cell migration

“…Our results that the open structure slow mobility TG2 band was present in both cytoplasmic and membrane fractions, and the higher mobility form was present only in cytoplasmic fractions (not in membrane fractions) in SHY TG2 and Panc-28 cells (Figure 5 B) suggests that a chaperone-like activity of Hsp70 might help in Ca 2+ -induced TG2 conversion, and interaction of Hsp-70 to the open slow mobility TG2 form might facilitate the transport of this form of TG2 from cytoplasm to plasma membrane. Previous studies indicate that acetylation [ 46 ] and ubiquitination of TG2 [ 47 ] inhibit its transamidation activity and degrade the protein into smaller fragments. In our studies increased transamidation activity by resveratrol and absence of smaller proteolytic fragments of TG2 suggest that resveratrol does not induce the acetylation and ubiquitination of TG2.…”

Cellular Functions of Tissue Transglutaminase

“…Likewise, S-nitrosylation of the cysteine residues by nitric oxide both in vitro (Lai et al, 2001) and in the vasculature (Santhanam et al, 2010) was shown to inhibit transamidating activity of TG2. Another posttranslational modification of TG2, acetylation, was also reported to suppress this TG2 activity in vitro (Lai et al, 2010). Finally, the apparently normal phenotype of TGM2 –/– mice does not suggest a major role for TG2 transamidating activity in vivo (De Laurenzi and Melino, 2001; Nanda et al, 2001).…”

PINK1 phosphorylates transglutaminase 2 and blocks its proteasomal degradation

“…TG2 is regulated by several posttranslational modifications, including phosphorylation, ubiquitination, and acetylation. For example, treatment with sulfosuccinimidyl acetate or aspirin induces acetylation of recombinant TG2 at Lys‐444, ‐468, and ‐663 residues, consequently decreasing TG2 cross‐linking enzyme activity (Lai et al, ). TG2 is also phosphorylated by protein kinase A at Ser‐216, which alters the TG2 function and protein–protein interactions (Wang et al, ).…”