Mechanism of Lys6 poly-ubiquitin specificity by the L. pneumophila deubiquitinase LotA

Gus D. Warren, Tomoe Kitao, Tyler G. Franklin, Justine V. Nguyen, Paul P. Geurink, Tomoko Kubori, Hiroki Nagai, Jonathan N. Pruneda

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The versatility of ubiquitination to control vast domains of eukaryotic biology is due, in part, to diversification through differently linked poly-ubiquitin chains. Deciphering signaling roles for some chain types, including those linked via K6, has been stymied by a lack of specificity among the implicated regulatory proteins. Forged through strong evolutionary pressures, pathogenic bacteria have evolved intricate mechanisms to regulate host ubiquitin during infection. Herein, we identify and characterize a deubiquitinase domain of the secreted effector LotA from Legionella pneumophila that specifically regulates K6-linked poly-ubiquitin. We demonstrate the utility of LotA for studying K6 poly-ubiquitin signals. We identify the structural basis of LotA activation and poly-ubiquitin specificity and describe an essential “adaptive” ubiquitin-binding domain. Without LotA activity during infection, the Legionella-containing vacuole becomes decorated with K6 poly-ubiquitin as well as the AAA ATPase VCP/p97/Cdc48. We propose that LotA's deubiquitinase activity guards Legionella-containing vacuole components from ubiquitin-dependent extraction.

Original languageEnglish (US)
Pages (from-to)105-120.e5
JournalMolecular Cell
Issue number1
StatePublished - Jan 5 2023


  • Legionella pneumophila
  • VCP/p97/Cdc48
  • bacterial effector
  • deubiquitinase
  • ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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