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.

Stabilizing transglutaminase 2 in the open conformation results in reactive astrocytes being more neurosupportive

“…To begin to elucidate the mechanisms underlying the effects of VA4 treatment, we tested whether VA4 modulates the interaction of TG2 and Zbtb7a, a transcription factor that we previously identified as a TG2 interactor (Emerson et al 2023). Based on results of our IP experiments, and the established roles of TG2 for regulating gene expression (Elahi et al 2021, Filiano et al 2008, Gundemir et al 2013, Kim et al 2021, McConoughey et al 2010, Monteagudo et al 2018, Rossin et al 2023, and Zbtb7a for regulating chromatin accessibility (Pittol et al 2018, Monteagudo et al 2018, we hypothesized that TG2 binds with transcription factors such as Zbtb7a to influence chromatin accessibility in astrocytes. In line with this hypothesis, VA4 significantly decreases TG2 binding to Zbtbt7a.…”

“…2013, Kim et al 2021, McConoughey et al . 2010, Monteagudo et al 2018, Rossin et al 2023), and Zbtb7a for regulating chromatin accessibility (Pittol et al 2018, Monteagudo et al 2018), we hypothesized that TG2 binds with transcription factors such as Zbtb7a to influence chromatin accessibility in astrocytes. In line with this hypothesis, VA4 significantly decreases TG2 binding to Zbtbt7a.…”

“…2011, Farrelly et al 2019, Filiano et al 2008, Gundemir et al 2013, Gundemir and Johnson 2009, Lepack et al 2020, McConoughey et al 2010, Milakovic et al . 2004, Rossin et al 2023, Rroji et al . 2021).…”

“…However, further work is needed to determine whether VA4 alters TG2 translocation to the nucleus, which could alternatively lead to transcriptional and functional changes associated with TG2 deletion. Further work also needs to be done to determine the relative contributions of TG2’s ability to catalytically modify nuclear proteins and TG2’s nuclear scaffolding function to its overall effect in astrocytes of upregulating neurosupportive function in response to stress (Rossin et al 2023, Basso and Ratan 2013, Farrelly et al 2019).…”

“…Additionally, in the closed conformation, TG2 can function as a scaffold for protein-protein interactions at the cell surface and in the nucleus, with well-described roles, for example, in cell-ECM interactions and chromatin regulation (Chen and Mehta 1999, Gundemir et al 2012, Akimov and Belkin 2001, Begg et al 2006, Farrelly et al 2019, Eckert et al . 2014, Rossin et al . 2023, van Strien et al .…”