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

Yunes-Medina, Laura; Feola, Julianne; Johnson, Gail V.W.

doi:10.1097/wnr.0000000000000895

Cited by 14 publications

(16 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have shown that nuclear TG2 is primarily in the chromatin fraction (Lesort, Attanavanich, Zhang, & Johnson, ) and that in neurons TG2 supports cell viability with significantly increased nuclear levels in response to hypoxic stress (Filiano et al., , ; Yunes‐Medina et al., ). Although it is clear that TG2 mediates gene expression in neurons (Yunes‐Medina et al., ), it is not known whether these effects are direct or indirect.…”

Section: Resultsmentioning

confidence: 95%

“…In the central nervous system (CNS), TG2 is expressed in neurons and glial cells (Maggio, Sellitti, Capano, & Papa, ; Monsonego et al., ; Yunes‐Medina, Feola, & Johnson, ), and a predominantly cytosolic localization of TG2 has been observed in both cell types. However, in response to stress, nuclear TG2 levels in neurons increase while the levels in astrocytic nuclei decrease (Yunes‐Medina et al., ). This differential response of nuclear TG2 in astrocytes and neurons is closely associated with the viability of these two cell types under stress.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons

Tang

Harrison

et al. 2018

Eur J of Neuroscience

View full text Add to dashboard Cite

Transglutaminase 2 (TG2) is a protein that modulates neuronal survival processes. Although TG2 is primarily cytosolic, data have suggested the nuclear localization of TG2 is strongly associated with neuronal viability. Depletion of TG2 in neurons results in neurite retraction and loss of viability, which is likely due to a dysregulation in gene expression. To begin to understand how TG2 regulates neuronal gene expression, chromatin immunoprecipitation was performed in neurons with TG2 overexpression. The resulting genomic DNA was recovered and sequenced. Bioinformatics analyses revealed that a signature DNA motif was enriched in the TG2 immunoprecipitated genomic DNA. In particular, this motif strongly mapped to a region proximate to the gene Ctss (cathepsin S). Knockdown of TG2 resulted in a significant increase in cathepsin S expression, which preceded the loss of neuronal viability. This is the first demonstration that TG2 directly associates with genomic DNA and regulates gene expression in neurons. Given that expression of cathepsin S is increased in neurological disease states, our data suggest that TG2 may play a role in promoting neuron health in part by repressing the expression of cathepsin S. Overall these data provide new insights into the function of nuclear TG2 in neurons.

show abstract

Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons

Tang

Harrison

et al. 2018

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…Although there are similarities between the processes involved in neurite and filopodia dynamics, it is likely that TG2 differentially affects these cellular events in neurons and astrocytes. For example, TG2 is externalized by astrocytes, but not neurons (van Strien, Baron, et al, ; van Strien, Breve, et al, ; Yunes‐Medina et al, ), and the interaction of TG2 with the ECM plays an important role in modifying the ability of astrocytes to extend their filopodia and migrate (van Strien, Baron, et al, ; van Strien, Breve, et al, ).…”

Section: Tg2 Supports Neuronal Survivalmentioning

confidence: 99%

“…Clearly further studies are needed to understand why TG2 differentially affects survival in neurons and astrocytes, although one clue may be that in response to stress the localization patterns of TG2 differ significantly. In hypoxic conditions the levels of TG2 in the nucleus of neurons increase significantly, while in astrocytes there is a significant decrease in nuclear TG2 (Yunes-Medina et al 2017). This data provides a conceptual framework in which nuclear TG2 is protective while cytosolic TG2 is detrimental to survival, due to increased transamidating activity resulting from the open conformation assumed by TG2.…”

Section: The Relationship Between Tg2 Localization Activation State mentioning

confidence: 99%

Transglutaminase 2: Friend or foe? The discordant role in neurons and astrocytes

Quinn

Yunes-Medina

Johnson

2018

J of Neuroscience Research

Self Cite

View full text Add to dashboard Cite

Members of the transglutaminase family catalyze the formation of isopeptide bonds between a polypeptide-bound glutamine and a low molecular weight amine (e.g., spermidine) or the ɛ-amino group of a polypeptide-bound lysine. Transglutaminase 2 (TG2), a prominent member of this family, is unique because in addition to being a transamidating enzyme, it exhibits numerous other activities. As a result, TG2 plays a role in many physiological processes, and its function is highly cell type specific and relies upon a number of factors, including conformation, cellular compartment location, and local concentrations of Ca and guanine nucleotides. TG2 is the most abundant transglutaminase in the central nervous system (CNS) and plays a pivotal role in the CNS injury response. How TG2 affects the cell in response to an insult is strikingly different in astrocytes and neurons. In neurons, TG2 supports survival. Overexpression of TG2 in primary neurons protects against oxygen and glucose deprivation (OGD)-induced cell death and in vivo results in a reduction in infarct volume subsequent to a stroke. Knockdown of TG2 in primary neurons results in a loss of viability. In contrast, deletion of TG2 from astrocytes results in increased survival following OGD and improved ability to protect neurons from injury. Here, a brief overview of TG2 is provided, followed by a discussion of the role of TG2 in transcriptional regulation, cellular dynamics, and cell death. The differing roles TG2 plays in neurons and astrocytes are highlighted and compared to how TG2 functions in other cell types.

show abstract

“…Expression of TG2 constructs with a nuclear export sequence (NES) afforded no protective effects against OGD-induced cell death (Gundemir and Johnson, 2009). When comparing the localization of TG2 in neurons and astrocytes it was found that exposure to hypoxia resulted in a significant increase in nuclear TG2 levels in neurons, but in astrocytes just the opposite was true; nuclear levels decreased significantly with hypoxia (Yunes-Medina et al, 2017). Further, in a mouse model, overexpressing TG2 in neurons significantly decreased infarct volumes following a middle cerebral artery ligation (MCAL)-induced stroke concurrent with increases in nuclear TG2 levels (Filiano et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Depletion of transglutaminase 2 in neurons alters expression of extracellular matrix and signal transduction genes and compromises cell viability

Yunes-Medina

Paciorkowski

Nuzbrokh

et al. 2018

Molecular and Cellular Neuroscience

Self Cite

View full text Add to dashboard Cite

The protein transglutaminase 2 (TG2) has been implicated as a modulator of neuronal viability. TG2's role in mediating cell survival processes has been suggested to involve its ability to alter transcriptional events. The goal of this study was to examine the role of TG2 in neuronal survival and to begin to delineate the pathways it regulates. We show that depletion of TG2 significantly compromises the viability of neurons in the absence of any stressors. RNA sequencing revealed that depletion of TG2 dysregulated the expression of 86 genes with 59 of these being upregulated. The genes that were upregulated by TG2 knockdown were primarily involved in extracellular matrix function, cell signaling and cytoskeleton integrity pathways. Finally, depletion of TG2 significantly reduced neurite length. These findings suggest for the first time that TG2 plays a crucial role in mediating neuronal survival through its regulation of genes involved in neurite length and maintenance.

show abstract

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

Cited by 14 publications

References 34 publications

Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons

Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons

Transglutaminase 2: Friend or foe? The discordant role in neurons and astrocytes

Depletion of transglutaminase 2 in neurons alters expression of extracellular matrix and signal transduction genes and compromises cell viability

Contact Info

Product

Resources

About