The glycerol channel Fps1p mediates the uptake of arsenite and antimonite in Saccharomyces cerevisiae

Autor: Markus J. Tamás, Cyrille C. Chéry, Marijn Van Hulle, Rita Cornelis, Robert W. Wysocki, Johan M. Thevelein, Donata Wawrzycka
Rok vydání: 2001
Předmět:
Zdroj: Molecular microbiology. 40(6)
ISSN: 0950-382X
Popis: Laboratorium voor Moleculaire Celbiologie, KatholiekeUniversiteit Leuven, Kasteelpark Arenberg 31, B-3001Leuven-Heverlee, Flanders, Belgium.SummaryThe Saccharomyces cerevisiae FPS1 gene encodes aglycerol channel protein involved in osmoregulation.We present evidence that Fps1p mediates influx of thetrivalent metalloids arsenite and antimonite in yeast.Deletion of FPS1 improves tolerance to arsenite andpotassium antimonyl tartrate. Under high osmolarityconditions, when the Fps1p channel is closed, wild-type cells show the same degree of As(III) and Sb(III)tolerance as the fps1Dmutant. Additional deletion ofFPS1 in mutants defective in arsenite and antimonitedetoxification partially suppresses their hypersensi-tivity to metalloid salts. Cells expressing a constitu-tively open form of the Fps1p channel are highlysensitive to both arsenite and antimonite. We alsoshow by direct transport assays that arsenite uptakeis mediated by Fps1p. Yeast cells appear to controlthe Fps1p-mediated pathway of metalloid uptake, asexpression of the FPS1 gene is repressed upon As(III)and Sb(III) addition. To our knowledge, this is the firstreport describing a eukaryotic uptake mechanism forarsenite and antimonite and its involvement inmetalloid tolerance.IntroductionArsenic and antimony are toxic metalloids with a longhistory of usage as therapeutic agents. Paul Ehrlichshowedatthebeginningofthetwentiethcenturythatsomeinfectious diseases such as syphilis and trypanosomiasiscould be treated successfully with organic derivatives ofarsenic (Xu et al., 1998). In addition, potassium arsenitewas used for controlling the level of leucocytes in patientssuffering from chronic myelocytic leukaemia until the1930s (Forkner and McNair-Scott, 1931). Although thesedrugs have been replaced with more effective and lesstoxic agents, the organic arsenical melarsoprol is still inuse for the treatment of sleeping sickness. Likewise, allforms of leishmaniasis are treated with drugs containingthe related metalloid antimony (Borst and Ouellette,1995).Arsenic trioxide has been shown recently to be a highlyeffective and relatively safe drug in treating patients withacute promyelocytic leukaemia who are resistant toconventional chemotherapy (Shen et al., 1997; Soignetetal.,1998).Invitrostudieshaverevealedthatantimonialsand melarsoprol inhibit growth and induce apoptosis ofleukaemia cells in a similar way to arsenic trioxide andcould therefore be used in antileukaemic therapy (Mu¨lleret al., 1998; Wang et al., 1998; Rousselot et al., 1999).There is promising evidence that arsenic trioxide causesapoptosis of both haematologic and solid tumour celllines in vitro and that it might also be effective in vivo(Ko¨nig et al., 1997; Yang et al., 1999; Zhang et al., 1999).However, the development of clinical resistance in somepatients treated with arsenic trioxide suggests thepresence of resistance mechanisms (Soignet et al.,1998). Hence, it is of interest to elucidate the molecularmechanisms involved in resistance to both arsenic andantimony in eukaryotes.Although tolerance to arsenic and antimony salts iswelldefined inbacteria, therehasbeenlittle informationonsuch mechanisms in eukaryotic cells (Silver, 1998; Rosen,1999a, b). Several genes of the eukaryotic modelorganism Saccharomyces cerevisiae (baker’s yeast)have been shown recently to affect metalloid tolerance,which hascontributed toa rapid progress in understandingthis phenomenon.Arsenite [As(III)] and arsenate [As(V)] tolerance in yeastis mediated by a cluster of three genes: ACR1 (ARR1,YAP8), ACR2 (ARR2) and ACR3 (ARR3) (Bobrowiczet al., 1997). The ACR1 gene encodes a transcriptionfactor belonging to the fungus-specific Yap family of bZIPproteins (Fernandes et al., 1997). Acr1p appears to beinvolved in controlling the induction of ACR2 and ACR3
Databáze: OpenAIRE
Externí odkaz: