title: Targeting eEF1A by a Legionella pneumophila effector leads to inhibition of protein synthesis and induction of host stress response.
abstract: The Legionella pneumophila Dot/Icm type IV secretion system is essential for the biogenesis of a phagosome that supports bacterial multiplication, most likely via the functions of its protein substrates. Recent studies indicate that fundamental cellular processes, such as vesicle trafficking, stress response, autophagy and cell death, are modulated by these effectors. However, how each translocated protein contributes to the modulation of these pathways is largely unknown. In a screen to search substrates of the Dot/Icm transporter that can cause host cell death, we identified a gene whose product is lethal to yeast and mammalian cells. We demonstrate that this protein, called SidI, is a substrate of the Dot/Icm type IV protein transporter that targets the host protein translation process. Our results indicate that SidI specifically interacts with eEF1A and eEF1Bgamma, two components of the eukaryotic protein translation elongation machinery and such interactions leads to inhibition of host protein synthesis. Furthermore, we have isolated two SidI substitution mutants that retain the target binding activity but have lost toxicity to eukaryotic cells, suggesting potential biochemical effect of SidI on eEF1A and eEF1Bgamma. We also show that infection by L. pneumophila leads to eEF1A-mediated activation of the heat shock regulatory protein HSF1 in a virulence-dependent manner and deletion of sidI affects such activation. Moreover, similar response occurred in cells transiently transfected to express SidI. Thus, inhibition of host protein synthesis by specific effectors contributes to the induction of stress response in L. pneumophila-infected cells.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Shen
authors.forename: Simran
authors.initials: S
authors.lastname: Banga
authors.forename: Yancheng
authors.initials: Y
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Ilya
authors.initials: I
authors.lastname: Shamovsky
authors.forename: Evgeny
authors.initials: E
authors.lastname: Nudler
authors.forename: Zhao-Qing
authors.initials: ZQ
authors.lastname: Luo
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002468:Cell Physiological Phenomena; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D000076249:Heat Shock Transcription Factors; D054884:Host-Pathogen Interactions; D006801:Humans; D016952:Legionella pneumophila / Q000472:pathogenicity*; D051379:Mice; D020125:Mutation, Missense; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D014176:Protein Biosynthesis; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D013312:Stress, Physiological; D014157:Transcription Factors / Q000096:biosynthesis; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D020648:Peptide Elongation Factor 1; D014157:Transcription Factors; D037521:Virulence Factors