Characterization of distinct sub-cellular location of transglutaminase type II: changes in intracellular distribution in physiological and pathological states

Abstract

Transglutaminase type II (TG2) is a pleiotropic enzyme that exhibits various activities unrelated to its originally identified functions. Apart from post-translational modifications of proteins (peculiar to the transglutaminase family enzymes), TG2 is involved in diverse biological functions, including cell death, signaling, cytoskeleton rearrangements, displaying enzymatic activities, G-protein and non-enzymatic biological functions. It is involved in a variety of human diseases such as celiac disease, diabetes, neurodegenerative diseases, inflammatory disorders and cancer. Regulatory mechanisms might exist through which cells control multifunctional protein expression as a function of their sub-cellular localization. The definition of the tissue and cellular distribution of such proteins is important for the determination of their function(s). We investigate the sub-cellular localization of TG2 by confocal and immunoelectron microscopy techniques in order to gain an understanding of its properties. The culture conditions of human sarcoma cells (2fTGH cells), human embryonic kidney cells (HEK293TG) and human neuroblastoma cells (SK-n-BE(2)) are modulated to induce various stimuli. Human tissue samples of myocardium and gut mucosa (diseased and healthy) are also analyzed. Immuno-gold labeling indicates that TG2 is localized in the nucleus, mitochondria and endoplasmic reticulum under physiological conditions but that this is not a stable association, since different locations or different amounts of TG2 can be observed depending on stress stimuli or the state of activity of the cell. We describe a possible unrecognized location of TG2. Our findings thus provide useful insights regarding the functions and regulation of this pleiotropic enzyme.

TG2 regulates the heat‐shock response by the post‐translational modification of HSF1

“…Indeed, recent compelling evidence places TG2 within the regulation of main pathways controlling the proteome homeostasis as autophagy, proteasome and exosomes . In keeping with this, there is a vast literature describing the deregulation of this enzyme during the pathogenesis of major human diseases (neurodegenerative, liver and respiratory disorders as well as cancer) in which there is a deregulated proteostasis that can be improved by modulators of TG2 activity . In spite of differences related to cell‐ and tissue‐specific disease context, these disorders share common features of unbalanced cell adaptation to either cell autonomous or environmental stress.…”

Transglutaminase 2 modulation of NF-κB signaling in astrocytes is independent of its ability to mediate astrocytic viability in ischemic injury

“…TG2 belongs to a class of enzymes known as the transglutaminases. TG2 is unique in this class of proteins, as it is ubiquitously expressed in all cell types within the brain, and can be found in most subcellular compartments (Espitia Pinzon et al, 2014; Grosso and Mouradian, 2012; Hilton et al, 1997; Hwang et al, 2009; Kim et al, 1999; Lesort et al, 1998; Lesort et al, 1999; Lorand and Graham, 2003; Mastroberardino et al, 2006; Piacentini et al, 2002; Piacentini et al, 2014; van Strien et al, 2011a; van Strien et al, 2011b). …”

Subcellular localization patterns of transglutaminase 2 in astrocytes and neurons are differentially altered by hypoxia

“…TG2 subcellular localization in particular can significantly impact its ability to mediate intracellular signaling processes that contribute to cell death and survival [11,12,14,15]. In the present study we have shown that hypoxia, a central nervous system (CNS) injury-relevant stressor, increases neuronal expression of TG2, but has no effect on the expression of TG2 in astrocytes.…”

“…Intriguingly the ability of TG2 to protect neurons against ischemic stress is not dependent on transamidating activity [7,8], while the ability of TG2 to facilitate astrocyte migration [9] or potentiate ischemic-induced cell death [10] requires TG2’s transamidating activity. Further, its ability to mediate cell death and survival processes has been suggested to be dependent, in part, on its subcellular localization [11–15]. In particular, targeting TG2 to the nucleus in various cell lines results in protection against a range of stressors [11–14].…”