The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation

Sara Altuntas, Federica Rossin, Claudia Marsella, Manuela D'Eletto, Laura Diaz Hidalgo, Maria Grazia Farrace, Michelangelo Campanella, Manuela Antonioli, Gian Maria Fimia, Mauro Piacentini

Research output: Contribution to journalArticle

Abstract

Autophagy is a self-degradative physiological process by which the cell removes worn-out or damaged components. Constant at basal level it may become highly active in response to cellular stress. The type 2 transglutaminase (TG2), which accumulates under stressful cell conditions, plays an important role in the regulation of autophagy and cells lacking this enzyme display impaired autophagy/mitophagy and a consequent shift their metabolism to glycolysis. To further define the molecular partners of TG2 involved in these cellular processes, we analysed the TG2 interactome under normal and starved conditions discovering that TG2 interacts with various proteins belonging to different functional categories. Herein we show that TG2 interacts with pyruvate kinase M2 (PKM2), a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity. Interestingly, the ablation of PKM2 led to the decrease of intracellular TG2's transamidating activity paralleled by an increase of its tyrosine phosphorylation. Along with this, a significant decrease of ULK1 and Beclin1 was also recorded, thus suggesting a block in the upstream regulation of autophagosome formation. These data suggest that the PKM2/TG2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells.

Original languageEnglish
Pages (from-to)44941-44954
Number of pages14
JournalOncotarget
Volume6
Issue number42
DOIs
Publication statusPublished - 2015

Keywords

  • Autophagy
  • Beclin1
  • LC3
  • Pyruvate kinase M2
  • Transglutaminase type 2

ASJC Scopus subject areas

  • Oncology

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    Altuntas, S., Rossin, F., Marsella, C., D'Eletto, M., Hidalgo, L. D., Farrace, M. G., Campanella, M., Antonioli, M., Fimia, G. M., & Piacentini, M. (2015). The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation. Oncotarget, 6(42), 44941-44954. https://doi.org/10.18632/oncotarget.6759