Survival of mycobacteria depends on proteasome-mediated amino acid recycling under nutrient limitation

Yifat Elharar, Ziv Roth, Inna Hermelin, Alexandra Moon, Gabriella Peretz, Yael Shenkerman, Marina Vishkautzan, Isam Khalaila, Eyal Gur

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Intracellular protein degradation is an essential process in all life domains. While in all eukaryotes regulated protein degradation involves ubiquitin tagging and the 26S-proteasome, bacterial prokaryotic ubiquitin-like protein (Pup) tagging and proteasomes are conserved only in species belonging to the phyla Actinobacteria and Nitrospira. In Mycobacterium tuberculosis, the Pup-proteasome system (PPS) is important for virulence, yet its physiological role in non-pathogenic species has remained an enigma. We now report, using Mycobacterium smegmatis as a model organism, that the PPS is essential for survival under starvation. Upon nitrogen limitation, PPS activity is induced, leading to accelerated tagging and degradation of many cytoplasmic proteins. We suggest a model in which the PPS functions to recycle amino acids under nitrogen starvation, thereby enabling the cell to maintain basal metabolic activities. We also find that the PPS auto-regulates its own activity via pupylation and degradation of its components in a manner that promotes the oscillatory expression of PPS components. As such, the destructive activity of the PPS is carefully balanced to maintain cellular functions during starvation. Synopsis In bacteria, the Pup-proteasome system (PPS) tags and degrades cellular proteins in a manner analogous to that of the eukaryotic ubiquitin-proteasome system. Molecular and genetic analysis of the PPS in Mycobacterium smegmatis now reveal that this system is essential under nitrogen starvation conditions and carefully regulated under such conditions to recycle amino acids in a controlled manner. Under nitrogen starvation conditions: A PPS-deficient mutant presented reduced survival. Both Pup-tagging and proteasomal degradation were accelerated. The PPS is auto-regulated via pupylation and degradation of its own components. PPS auto-regulation results in oscillatory expression of its components. The Mycobacterium smegmatis Pup-proteasome protein degradation system is needed for amino acids recycling under nitrogen starvation conditions allowing for the maintenance of basal metabolic activities and survival under prolonged nutrient limitation.

Original languageEnglish
Pages (from-to)1802-1814
Number of pages13
JournalEMBO Journal
Issue number16
StatePublished - 18 Aug 2014


  • mycobacteria
  • nitrogen limitation
  • proteasome
  • proteolysis
  • pupylation

ASJC Scopus subject areas

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


Dive into the research topics of 'Survival of mycobacteria depends on proteasome-mediated amino acid recycling under nutrient limitation'. Together they form a unique fingerprint.

Cite this