Transglutaminase 2 is involved in autophagosome maturation

Manuela D'Eletto, Maria Grazia Farrace, Laura Falasca, Valentina Reali, Serafina Oliverio, Gennaro Melino, Martin Griffin, Gian Maria Fimia, Mauro Piacentini

Research output: Contribution to journalArticle

Abstract

Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but it is enhanced in response to stress, e.g. nutrient deprivation, hypoxia, mitochondrial dysfunction and infection. "Tissue" transglutaminase (TG2) accumulates, both in vivo and in vitro, to high levels in cells under stressful conditions. Therefore, in this study, we investigated whether TG2 could also play a role in the autophagic process. To this end, we used TG2 knockout mice and cell lines in which the enzyme was either absent or overexpressed. The ablation of TG2 protein both in vivo and in vitro, resulted in an evident accumulation of microtubule-associated protein 1 light chain 3 cleaved isoform II (LC3 II) on pre-autophagic vesicles, suggesting a marked induction of autophagy. By contrast, the formation of the acidic vesicular organelles in the same cells was very limited, indicating an impairment of the final maturation of autophagolysosomes. In fact, the treatment of TG2 proficient cells with NH4Cl, to inhibit lysosomal activity, led to a marked accumulation of LC3 II and damaged mitochondria similar to what we observed in TG2-deficient cells. These data indicate a role for TG2-mediated post-translational modifications of proteins in the maturation of autophagosomes accompanied by the accumulation of many damaged mitochondria.
LanguageEnglish
Pages1145-1154
Number of pages10
JournalAutophagy
Volume5
Issue number8
DOIs
Publication statusPublished - 16 Nov 2009

Fingerprint

Autophagy
Organelles
Mitochondria
Protein Isoforms
Light
Microtubule-Associated Proteins
Post Translational Protein Processing
Knockout Mice
Proteins
Cell Line
Food
transglutaminase 2
Autophagosomes
Enzymes
Infection
In Vitro Techniques

Keywords

  • animals
  • autophagy
  • cross-linking reagents
  • mammalianembryo
  • fibroblasts
  • flow cytometry
  • fluorescent antibody technique
  • GTP-binding proteins
  • gene knockout techniques
  • humans
  • lysosomes
  • membrane fusion
  • mice
  • microtubule-associated proteins
  • myocardium
  • phagosomes
  • secretory vesicles
  • staining and labeling
  • transglutaminases

Cite this

D'Eletto, M., Farrace, M. G., Falasca, L., Reali, V., Oliverio, S., Melino, G., ... Piacentini, M. (2009). Transglutaminase 2 is involved in autophagosome maturation. Autophagy, 5(8), 1145-1154. https://doi.org/10.4161/auto.5.8.10040
D'Eletto, Manuela ; Farrace, Maria Grazia ; Falasca, Laura ; Reali, Valentina ; Oliverio, Serafina ; Melino, Gennaro ; Griffin, Martin ; Fimia, Gian Maria ; Piacentini, Mauro. / Transglutaminase 2 is involved in autophagosome maturation. In: Autophagy. 2009 ; Vol. 5, No. 8. pp. 1145-1154.
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D'Eletto, M, Farrace, MG, Falasca, L, Reali, V, Oliverio, S, Melino, G, Griffin, M, Fimia, GM & Piacentini, M 2009, 'Transglutaminase 2 is involved in autophagosome maturation' Autophagy, vol. 5, no. 8, pp. 1145-1154. https://doi.org/10.4161/auto.5.8.10040

Transglutaminase 2 is involved in autophagosome maturation. / D'Eletto, Manuela; Farrace, Maria Grazia; Falasca, Laura; Reali, Valentina; Oliverio, Serafina; Melino, Gennaro; Griffin, Martin; Fimia, Gian Maria; Piacentini, Mauro.

In: Autophagy, Vol. 5, No. 8, 16.11.2009, p. 1145-1154.

Research output: Contribution to journalArticle

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AU - D'Eletto, Manuela

AU - Farrace, Maria Grazia

AU - Falasca, Laura

AU - Reali, Valentina

AU - Oliverio, Serafina

AU - Melino, Gennaro

AU - Griffin, Martin

AU - Fimia, Gian Maria

AU - Piacentini, Mauro

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N2 - Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but it is enhanced in response to stress, e.g. nutrient deprivation, hypoxia, mitochondrial dysfunction and infection. "Tissue" transglutaminase (TG2) accumulates, both in vivo and in vitro, to high levels in cells under stressful conditions. Therefore, in this study, we investigated whether TG2 could also play a role in the autophagic process. To this end, we used TG2 knockout mice and cell lines in which the enzyme was either absent or overexpressed. The ablation of TG2 protein both in vivo and in vitro, resulted in an evident accumulation of microtubule-associated protein 1 light chain 3 cleaved isoform II (LC3 II) on pre-autophagic vesicles, suggesting a marked induction of autophagy. By contrast, the formation of the acidic vesicular organelles in the same cells was very limited, indicating an impairment of the final maturation of autophagolysosomes. In fact, the treatment of TG2 proficient cells with NH4Cl, to inhibit lysosomal activity, led to a marked accumulation of LC3 II and damaged mitochondria similar to what we observed in TG2-deficient cells. These data indicate a role for TG2-mediated post-translational modifications of proteins in the maturation of autophagosomes accompanied by the accumulation of many damaged mitochondria.

AB - Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but it is enhanced in response to stress, e.g. nutrient deprivation, hypoxia, mitochondrial dysfunction and infection. "Tissue" transglutaminase (TG2) accumulates, both in vivo and in vitro, to high levels in cells under stressful conditions. Therefore, in this study, we investigated whether TG2 could also play a role in the autophagic process. To this end, we used TG2 knockout mice and cell lines in which the enzyme was either absent or overexpressed. The ablation of TG2 protein both in vivo and in vitro, resulted in an evident accumulation of microtubule-associated protein 1 light chain 3 cleaved isoform II (LC3 II) on pre-autophagic vesicles, suggesting a marked induction of autophagy. By contrast, the formation of the acidic vesicular organelles in the same cells was very limited, indicating an impairment of the final maturation of autophagolysosomes. In fact, the treatment of TG2 proficient cells with NH4Cl, to inhibit lysosomal activity, led to a marked accumulation of LC3 II and damaged mitochondria similar to what we observed in TG2-deficient cells. These data indicate a role for TG2-mediated post-translational modifications of proteins in the maturation of autophagosomes accompanied by the accumulation of many damaged mitochondria.

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KW - lysosomes

KW - membrane fusion

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KW - microtubule-associated proteins

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D'Eletto M, Farrace MG, Falasca L, Reali V, Oliverio S, Melino G et al. Transglutaminase 2 is involved in autophagosome maturation. Autophagy. 2009 Nov 16;5(8):1145-1154. https://doi.org/10.4161/auto.5.8.10040