Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy

Agata Desantis, Tiziana Bruno, Valeria Catena, Francesca De Nicola, Frauke Goeman, Simona Iezzi, Cristina Sorino, Maurilio Ponzoni, Gianluca Bossi, Vincenzo Federico, Francesca La Rosa, Maria Rosaria Ricciardi, Elena Lesma, Paolo D Onorio De Meo, Tiziana Castrignanò, Maria Teresa Petrucci, Francesco Pisani, Marta Chesi, P. Leif Bergsagel, Aristide FloridiGiovanni Tonon, Claudio Passananti, Giovanni Blandino, Maurizio Fanciulli

Research output: Contribution to journalArticle

Abstract

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che-1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress-induced autophagy. Strikingly, Che-1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response. Synopsis The RNA polymerase-binding protein Che-1 inhibits the mTOR pathway in response to stress, thereby sustaining autophagy and multiple myeloma cell growth. Che-1 inhibits mTOR activity in response to cellular stress. Che-1 sustains Redd1 and Deptor expressions. Che-1 regulates autophagy by inhibiting mTORC1 activity. Che-1 expression increases during multiple myeloma progression and is required for cell survival. The RNA polymerase-binding protein Che-1 inhibits the mTOR pathway in response to stress, thereby sustaining autophagy and multiple myeloma cell growth.

Original languageEnglish
Pages (from-to)1214-1230
Number of pages17
JournalEMBO Journal
Volume34
Issue number9
DOIs
Publication statusPublished - May 5 2015

Keywords

  • autophagy
  • Che-1
  • mTOR
  • multiple myeloma

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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    Desantis, A., Bruno, T., Catena, V., De Nicola, F., Goeman, F., Iezzi, S., Sorino, C., Ponzoni, M., Bossi, G., Federico, V., La Rosa, F., Ricciardi, M. R., Lesma, E., De Meo, P. D. O., Castrignanò, T., Petrucci, M. T., Pisani, F., Chesi, M., Bergsagel, P. L., ... Fanciulli, M. (2015). Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy. EMBO Journal, 34(9), 1214-1230. https://doi.org/10.15252/embj.201489920