Proapoptotic requirement of ribosomal protein L11 in ribosomal stress-challenged cortical neurons

Lukasz P. Slomnicki, Justin Hallgren, Aruna Vashishta, Scott C. Smith, Steven R. Ellis, Michal Hetman

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

While impaired ribosomal biogenesis is observed in neurodegenerative diseases, its pathogenic contributions are not clear. For instance, it is well established that in rodent neurons, genetic inhibition of RNA-polymerase 1 that transcribes rRNA results in structural disruption of the nucleolus, neuronal apoptosis, and neurodegeneration. However, in most neurodegenerative diseases, nucleolar morphology is unaffected. It is reported here that in primary cortical neurons from newborn rats, inhibition of ribosomal biogenesis by shRNAmediated knockdowns of several ribosomal proteins including S6, S14, or L4 resulted in p53-mediated apoptosis despite absence of structural disruption of the nucleolus. Conversely, knockdown of the RP L11, which in nonneuronal systems mediates p53 activation downstream of ribosomal stress, protected neurons against inhibition of ribosomal biogenesis but not staurosporine. Moreover, overexpression of L11 enhanced p53-driven transcription and increased neuronal apoptosis. In addition, inhibition of p53, or L11 knockdown, blocked apoptosis in response to the RNA analog 5- fluorouridine which perturbed nucleolar structure, inhibited ribosomal synthesis, and activated p53. Although the DNA double-strand break (DSB) inducer etoposide activated p53, nucleolar structure appeared intact. However, by activating the DNA damage response kinase ATM, etoposide increased 47S pre-rRNA levels, and enhanced nucleolar accumulation of nascent RNA, suggesting slower rRNA processing and/or increased Pol1 activity. In addition, shL11 reduced etoposideinduced apoptosis. Therefore, seemingly normal morphology of the neuronal nucleolus does not exclude presence of ribosomal stress. Conversely, targeting the ribosomal stressspecific signaling mediators including L11 offers a novel approach to uncover neurodegenerative contributions of deregulated ribosomal synthesis as exemplified in DSBchallenged neurons.

Original languageEnglish (US)
Pages (from-to)538-553
Number of pages16
JournalMolecular Neurobiology
Volume55
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Apoptosis
Neurons
Etoposide
Neurodegenerative Diseases
Ribosomal Protein S6
RNA
Staurosporine
Double-Stranded DNA Breaks
RNA Precursors
DNA-Directed RNA Polymerases
DNA Damage
Rodentia
Phosphotransferases
ribosomal protein L11

Keywords

  • Apoptosis
  • DNAdamage
  • Neurons
  • Nucleolus
  • Ribosomal proteins
  • p53

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Proapoptotic requirement of ribosomal protein L11 in ribosomal stress-challenged cortical neurons. / Slomnicki, Lukasz P.; Hallgren, Justin; Vashishta, Aruna; Smith, Scott C.; Ellis, Steven R.; Hetman, Michal.

In: Molecular Neurobiology, Vol. 55, No. 1, 01.01.2018, p. 538-553.

Research output: Contribution to journalArticle

Slomnicki, Lukasz P. ; Hallgren, Justin ; Vashishta, Aruna ; Smith, Scott C. ; Ellis, Steven R. ; Hetman, Michal. / Proapoptotic requirement of ribosomal protein L11 in ribosomal stress-challenged cortical neurons. In: Molecular Neurobiology. 2018 ; Vol. 55, No. 1. pp. 538-553.
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