Trypanosomatid RACK1 orthologs show functional differences associated with translation despite similar roles in Leishmania pathogenesis

RACK1 proteins belong to the eukaryote WD40-repeat protein family and function as spatial regulators of multiple cellular events, including signaling pathways, the cell cycle and translation. For this latter role, structural and genetic studies indicate that RACK1 associates with the ribosome throug...

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Bibliographic Details
Published in:PloS one 2011-06, Vol.6 (6), p.e20710-e20710
Main Authors: Choudhury, Kohelia, Cardenas, Daviel, Pullikuth, Ashok K, Catling, Andrew D, Aiyar, Ashok, Kelly, Ben L
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Animals
Antigens, Protozoan - genetics
Antigens, Protozoan - metabolism
Biology
Cell cycle
Cell Cycle - physiology
Eukaryotes
Female
Genetic aspects
High temperature
Inhibitors
Kinases
Leishmania
Leishmania donovani
Leishmania major - cytology
Leishmania major - pathogenicity
Leishmania major - physiology
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Parasites
Parasitic diseases
Pathogenesis
Polyribosomes
Polyribosomes - metabolism
Protein Biosynthesis
Proteins
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Regulators
Residues
Ribosomal Proteins - genetics
Ribosomal Proteins - metabolism
Saccharomyces cerevisiae
Sequence Alignment
Signaling
Temperature
Transcription, Genetic
Translation
Trypanosoma brucei
Trypanosoma brucei brucei - genetics
Trypanosoma brucei brucei - metabolism
Trypanosoma cruzi
Viability
Virulence
Yeast
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Summary:RACK1 proteins belong to the eukaryote WD40-repeat protein family and function as spatial regulators of multiple cellular events, including signaling pathways, the cell cycle and translation. For this latter role, structural and genetic studies indicate that RACK1 associates with the ribosome through two conserved positively charged amino acids in its first WD40 domain. Unlike RACK1s, including Trypanosoma brucei RACK1 (TbRACK1), only one of these two positively-charged residues is conserved in the first WD40 domain of the Leishmania major RACK1 ortholog, LACK. We compared virulence-attenuated LACK single copy (LACK/-) L. major, with L. major expressing either two LACK copies (LACK/LACK), or one copy each of LACK and TbRACK1 (LACK/TbRACK1), to evaluate the function of these structurally distinct RACK1 orthologs with respect to translation, viability at host temperatures and pathogenesis. Our results indicate that although the ribosome-binding residues are not fully conserved in LACK, both LACK and TbRACK1 co-sedimented with monosomes and polysomes in LACK/LACK and LACK/TbRACK1 L. major, respectively. LACK/LACK and LACK/TbRACK1 strains differed in their sensitivity to translation inhibitors implying that minor sequence differences between the RACK1 proteins can alter their functional properties. While biochemically distinguishable, both LACK/LACK and LACK/TbRACK1 lines were more tolerant of elevated temperatures, resistant to translation inhibitors, and displayed robust pathogenesis in vivo, contrasting to LACK/- parasites.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0020710