Transglutaminase 2 interaction with small heat shock proteins mediate cell survival upon excitotoxic stress

Caccamo, Daniela, Condello, Salvatore, Ferlazzo, Nadia, Currò, Monica, Griffin, Martin and Ientile, Riccardo (2013). Transglutaminase 2 interaction with small heat shock proteins mediate cell survival upon excitotoxic stress. Amino Acids, 44 (1), pp. 151-159.


Transglutaminase 2 has been postulated to be involved in the pathogenesis of central nervous system neurodegenerative disorders. However, its role in neuronal cell death remains to be elucidated. Excitotoxicity is a common event underlying neurodegeneration. We aimed to evaluate the protein targets for transglutaminase 2 in cell response to NMDA-induced excitotoxic stress, using SH-SY5Y neuroblastoma cells which express high tranglutaminase 2 levels upon retinoic acid-driven differentiation toward neurons. NMDA-evoked calcium increase led to transglutaminase 2 activation that mediated cell survival, as at first suggested by the exacerbation of NMDA toxicity in the presence of R283, a synthetic competitive inhibitor of transglutaminase active site. Assays of R283-mediated transglutaminase inhibition showed the involvement of enzyme activity in NMDA-induced reduction in protein basal levels of pro-apoptotic caspase-3 and the stress protein Hsp20. However, this occurred in a way different from protein cross-linking, given that macromolecular assemblies were not observed in our experimental conditions for both proteins. Co-immunoprecipitation experiments provided evidence for the interaction, in basal conditions, between transglutaminase 2 and Hsp20, as well as between Hsp20 and Hsp27, a major anti-apoptotic protein promoting caspase-3 inactivation and degradation. NMDA treatment disrupted both these interactions that were restored upon transglutaminase 2 inhibition with R283. These results suggest that transglutaminase 2 might be protective against NMDA-evoked excitotoxic insult in neuronal-like SH-SY5Y cells in a way, independent from transamidation that likely involves its interaction with the complex Hsp20/Hsp27 playing a pro-survival role. © 2011 Springer-Verlag.

Publication DOI:
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Life & Health Sciences > Applied Health Research Group
Life & Health Sciences > Biomedical Sciences research group
Aston University (General)
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Uncontrolled Keywords: excitotoxicity,neuronal-like SH-SY5Y cells,small heat shock proteins,transglutaminase 2,transglutaminase inhibitor R283,Biochemistry,Clinical Biochemistry,Organic Chemistry
Published Date: 2013-01


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