The antibiotic gentamicin inhibits specific protein trafficking functions of the Arf1/2 family of GTPases.
Gentamicin is a highly efficacious antibiotic against Gram-negative bacteria. However, its usefulness in treating infections is compromised by its poorly understood renal toxicity. Toxic effects are also seen in a variety of other organisms. While the yeast Saccharomyces cerevisiae is relatively insensitive to gentamicin, mutations in any one of ∼20 genes cause a dramatic decrease in resistance. Many of these genes encode proteins important for translation termination or specific protein-trafficking complexes. Subsequent inspection of the physical and genetic interactions of the remaining gentamicin-sensitive mutants revealed a network centered on chitin synthase and the Arf GTPases. Further analysis has demonstrated that some conditional arf1 and gea1 alleles make cells hypersensitive to gentamicin under permissive conditions. These results suggest that one consequence of gentamicin exposure is disruption of Arf-dependent protein trafficking.
Lin
Lin
L
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Wagner
Mark C
MC
Cocklin
Ross
R
Kuzma
Alex
A
Harrington
Maureen
M
Molitoris
Bruce A
BA
Goebl
Mark G
MG
D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005839:Gentamicins / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
C102475:GEA1 protein, S cerevisiae; D005839:Gentamicins; D020662:Guanine Nucleotide Exchange Factors; D011500:Protein Synthesis Inhibitors; D029701:Saccharomyces cerevisiae Proteins; C116686:ARF2 protein, S cerevisiae; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors