Type 2 transglutaminase in the nucleus: the new epigenetic face of a cytoplasmic enzyme

Abstract

One of the major mysteries in science is how it is possible to pack the cellular chromatin with a total length of over 1 m, into a small sphere with a diameter of 5 mm "the nucleus", and even more difficult to envisage how to make it functional. Although we know that compaction is achieved through the histones, however, the DNA needs to be accessible to the transcription machinery and this is allowed thanks to a variety of very complex epigenetic mechanisms. Either DNA (methylation) or post-translational modifications of histone proteins (acetylation, methylation, ubiquitination and sumoylation) play a crucial role in chromatin remodelling and consequently on gene expression. Recently the serotonylation and dopaminylation of the histone 3, catalyzed by the Transglutaminase type 2 (TG2), has been reported. These novel post-translational modifications catalyzed by a predominantly cytoplasmic enzyme opens a new avenue for future investigations on the enzyme function itself and for the possibility that other biological amines, substrate of TG2, can influence the genome regulation under peculiar cellular conditions. In this review we analyzed the nuclear TG2's biology by discussing both its post-translational modification of various transcription factors and the implications of its epigenetic new face. Finally, we will focus on the potential impact of these events in human diseases.

Keywords: Epigenetic; Interactome; TG2; Transcriptional factors; cBAF.

Fig. 1

Western blot analysis showing cytosolic (left) and nuclear (right) protein expression of TG2 in A375 melanoma cells treated with doxorubicin for 16 and 24 h. GAPDH and TBP were used as loading control for cytosolic and nuclear fraction, respectively

Fig. 2

Representation of the transcriptional factors modified by TG2 and the enzymatic activities involved

Fig. 3

Protein–protein interaction network of the identified proteins into the nucleus of MEF cells. The network containing identified proteins was mapped using the STRING system (http://string-db.org/) based on evidence with different types. cBAF complex is showed in the inset

Fig. 4

Representation of cBAF complex proteins interacting with TG2 into the nucleus before and after doxorubicin treatment