The Actinobacterial mce4 Locus Encodes a Steroid Transporter

Bioinformatic analyses have suggested that Mce proteins in diverse actinobacteria are components of complex ATP-binding cassette transporter systems, comprising more than eight distinct proteins. In Mycobacterium tuberculosis, these proteins are implicated in interactions of this deadly pathogen with its human host. Here, we provide direct evidence that the Mce4 system of Rhodococcus jostii RHA1 is a steroid uptake system. Transcriptional analyses indicate that the system is encoded by an 11-gene operon, up-regulated 4.0-fold during growth on cholesterol versus on pyruvate. Growth of RHA1 on cholesterol and uptake of radiolabeled cholesterol both required expression of genes in the mce4 operon encoding two permeases plus eight additional proteins of unknown function. Cholesterol uptake was ATP-dependent and exhibited Michaelis-Menten kinetics with a Km of 0.6 ± 0.1 μm. This uptake system was also essential for growth of RHA1 on β-sitosterol, 5-α-cholestanol, and 5-α-cholestanone. Bioinformatic analysis revealed that all mce4 loci in sequenced genomes are linked to steroid metabolism genes. Thus, we predict that all Mce4 systems are steroid transporters. The transport function of the Mce4 system is consistent with proposed roles of cholesterol and its metabolism in the pathogenesis of M. tuberculosis. Bioinformatic analyses have suggested that Mce proteins in diverse actinobacteria are components of complex ATP-binding cassette transporter systems, comprising more than eight distinct proteins. In Mycobacterium tuberculosis, these proteins are implicated in interactions of this deadly pathogen with its human host. Here, we provide direct evidence that the Mce4 system of Rhodococcus jostii RHA1 is a steroid uptake system. Transcriptional analyses indicate that the system is encoded by an 11-gene operon, up-regulated 4.0-fold during growth on cholesterol versus on pyruvate. Growth of RHA1 on cholesterol and uptake of radiolabeled cholesterol both required expression of genes in the mce4 operon encoding two permeases plus eight additional proteins of unknown function. Cholesterol uptake was ATP-dependent and exhibited Michaelis-Menten kinetics with a Km of 0.6 ± 0.1 μm. This uptake system was also essential for growth of RHA1 on β-sitosterol, 5-α-cholestanol, and 5-α-cholestanone. Bioinformatic analysis revealed that all mce4 loci in sequenced genomes are linked to steroid metabolism genes. Thus, we predict that all Mce4 systems are steroid transporters. The transport function of the Mce4 system is consistent with proposed roles of cholesterol and its metabolism in the pathogenesis of M. tuberculosis. The mce genes of Mycobacterium tuberculosis have garnered much interest due to their demonstrated role in pathogenesis, although the function of these genes remains unclear. The first mce gene, now known as mce1A, was discovered when a DNA fragment cloned from M. tuberculosis into a noninvasive Escherichia coli strain enabled uptake of the latter bacterium by nonphagocytic mammalian epithelial (HeLa) cells and facilitated its phagocytosis by macrophages (1Arruda S. Bomfim G. Knights R. Huimabyron T. Riley L.W. Science. 1993; 261: 1454-1457Crossref PubMed Scopus (307) Google Scholar). A subsequent study showed that coating latex beads with the protein encoded by mce1A facilitated uptake of the beads by HeLa cells, and so the gene was designated mce for mammalian cell entry (2Chitale S. Ehrt S. Kawamura I. Fujimura T. Shimono N. Anand N. Lu S. Cohen-Gould L. Riley L.W. Cell. Microbiol. 2001; 3: 247-254Crossref PubMed Scopus (131) Google Scholar). The genome sequence of M. tuberculosis revealed four loci (mce1–4), each containing two yrbE genes followed by six mce genes (3Cole S.T. Brosch R. Parkhill J. Garnier T. Churcher C. Harris D. Gordon S.V. Eiglmeier K. Gas S. Barry III, C.E. Tekaia F. Badcock K. Basham D. Brown D. Chillingworth T. Connor R. Davies R. Devlin K. Feltwell T. Gentles S. Hamlin N. Holroyd S. Hornsby T. Jagels K. Krogh A. McLean J. Moule S. Murphy L. Oliver K. Osborne J. Quail M.A. Rajandream M.-A. Rogers J. Rutter S. Seeger K. Skelton J. Squares R. Squares S. Sulston J.E. Taylor K. Whitehead S. Barrell B.G. Nature. 1998; 396: 190-198Crossref Scopus (52) Google Scholar). The Mce proteins are predicted to have similar structures and to be secreted (4Mitra D. Saha B. Das D. Wiker H.G. Das A.K. Tuberculosis (Edinb.). 2005; 85: 337-345Crossref PubMed Scopus (13) Google Scholar), and Mce1A was localized to the surface of M. tuberculosis cells (2Chitale S. Ehrt S. Kawamura I. Fujimura T. Shimono N. Anand N. Lu S. Cohen-Gould L. Riley L.W. Cell. Microbiol. 2001; 3: 247-254Crossref PubMed Scopus (131) Google Scholar). The capacity to facilitate uptake by HeLa cells was further narrowed to a small region of the MceA1 protein (2Chitale S. Ehrt S. Kawamura I. Fujimura T. Shimono N. Anand N. Lu S. Cohen-Gould L. Riley L.W. Cell. Microbiol. 2001; 3: 247-254Crossref PubMed Scopus (131) Google Scholar, 5Casali N. Konieczny M. Schmidt M.A. Riley L.W. Infect. Immunol. 2002; 70: 6846-6852Crossref PubMed Scopus (36) Google Scholar, 6Lu S. Tager L.A. Chitale S. Riley L.W. Anal. Biochem. 2006; 353: 7-14Crossref PubMed Scopus (23) Google Scholar). Coating beads with either Mce3A or Mce3E also facilitated such uptake (7El-Shazly S. Ahmad S. Mustafa A.S. Raja Al-Attiyah R. Krajci D. J. Med. Microbiol. 2007; 56: 1145-1151Crossref PubMed Scopus (45) Google Scholar), whereas coating beads with Mce2A failed to do so (2Chitale S. Ehrt S. Kawamura I. Fujimura T. Shimono N. Anand N. Lu S. Cohen-Gould L. Riley L.W. Cell. Microbiol. 2001; 3: 247-254Crossref PubMed Scopus (131) Google Scholar). Together, these studies suggest that some of the Mce proteins might interact with host cells and play a role in uptake of M. tuberculosis by host cells. However, direct evidence for this function of Mce proteins is lacking. Mutational studies also support the involvement of Mce proteins in pathogenesis of M. tuberculosis. One genome-wide screen suggested that disruption of mce1 and mce4 genes causes early and late growth defects, respectively, in mice (8Sassetti C.M. Rubin E.J. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 12989-12994Crossref PubMed Scopus (1057) Google Scholar), and these phenotypes were confirmed with mce1D and yrbE4A deletion mutants, respectively (8Sassetti C.M. Rubin E.J. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 12989-12994Crossref PubMed Scopus (1057) Google Scholar, 9Joshi S.M. Pandey A.K. Capite N. Fortune S.M. Rubin E.J. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 11760-11765Crossref PubMed Scopus (133) Google Scholar, 10Pandey A.K. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 4376-4380Crossref PubMed Scopus (722) Google Scholar). Another genome-wide screen suggested that disruption of yrbE4A impairs macrophage infection (11Rosas-Magallanes V. Stadthagen-Gomez G. Rauzier J. Barreiro L.B. Tailleux L. Boudou F. Griffin R. Nigou J. Jackson M. Gicquel B. Neyrolles O. Infect. Immun. 2007; 75: 504-507Crossref PubMed Scopus (57) Google Scholar), and a yrbE4A deletion mutant was severely impaired in replication in interferon γ-activated macrophages (10Pandey A.K. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 4376-4380Crossref PubMed Scopus (722) Google Scholar). Disruption of any one of yrbE1B, mce2A, and mce3A genes in M. tuberculosis increased survival of intratrachaelly infected mice (12Gioffre A. Infante E. Aguilar D. de la Paz Santangelo M. Klepp L. Amadio A. Meikle V. Etchechoury I. Romano M.I. Cataldi A. Hernandez R.P. Bigi F. Microbes Infect. 2005; 7: 325-334Crossref PubMed Scopus (124) Google Scholar). Similarly, deletion of nearly entire mce3 or mce4 operons increased long term survival of mice following low dose aerosol infection, and the latter deletion also decreased bacterial burdens of the mice (13Senaratne R.H. Sidders B. Sequeira P. Saunders G. Dunphy K. Marjanovic O. Reader J.R. Lima P. Chan S. Kendall S. McFadden J. Riley L.W. J. Med. Microbiol. 2008; 57: 164Crossref PubMed Scopus (82) Google Scholar). By contrast, an mce1A deletion was hypervirulent in mice (14Shimono N. Morici L. Casali N. Cantrell S. Sidders B. Ehrt S. Riley L.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 15918-15923Crossref PubMed Scopus (175) Google Scholar). Thus, mce mutant strains have phenotypes generally supporting the involvement of these genes in pathogenesis, but the mutants exhibited disparate virulence phenotypes in different assays. Analysis of genome sequences indicated that diverse actinobacteria, including members of Mycobacterium, Nocardia, Rhodococcus, and Streptomyces, harbor mce loci (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar, 16McLeod M.M. Warren R.L. Hsiao W. W.L. Araki N. Myhre M. Fernandes C. Miyazawa D. Wong W. Lillquist A.L. Wang D. Dosanjh M. Hara H. Petrescu A. Morin R.D. Yang G. Stott J.M. Schein J.E. Shin H. Smailus D. Siddiqui A.S. Marra M.A. Jones S. J.M. Holt R. Brinkman F. S.L. Miyauchi K. Fukuda M. Davies J.E. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 15582-15587Crossref PubMed Scopus (499) Google Scholar). Moreover, PCR-based assays revealed the existence of mce4 loci in 11 of 20 Mycobacterium spp. screened (17Haile Y. Caugant D.A. Bjune G. Wiker H.G. FEMS Immunol. Med. Microbiol. 2002; 33: 125-132Crossref PubMed Google Scholar). The actinobacteria with mce loci include both pathogens and free-living bacteria, that the function of these genes is to Bioinformatic analyses (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar, F. Gordon S.V. Garnier T. Brosch R. Barrell B.G. S.T. PubMed Scopus Google indicated that the yrbE genes of all mce loci proteins with to components of ATP-binding cassette de transporters. The of is an with mce loci include genes encoding such to the a of transporter (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar). all actinobacteria containing mce loci were to also genes encoding to the mce on and S.M. Pandey A.K. Capite N. Fortune S.M. Rubin E.J. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 11760-11765Crossref PubMed Scopus (133) Google evidence that the and Mce4 proteins in M. tuberculosis are both linked to a encoded by a gene linked to either the mce1 or the mce4 suggest that mce loci a of However, direct evidence for this transport function ATP-binding cassette de mce loci also include two or four genes of the genes (14Shimono N. Morici L. Casali N. Cantrell S. Sidders B. Ehrt S. Riley L.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 15918-15923Crossref PubMed Scopus (175) Google Scholar). The latter genes have to as genes (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google is for to of M. tuberculosis M. J. PubMed Google Scholar), so we to the latter genes in mce loci as additional mce genes that the mce4 of Rhodococcus jostii RHA1 was a of genes up-regulated during growth on cholesterol R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). Moreover, we that RHA1 mutants with of either the genes to or the genes the to on to that the Mce4 system of RHA1 in cholesterol the mce4 of M. tuberculosis is also with cholesterol metabolism genes to in we the function for the Mce4 systems in both with Pandey and Sassetti (10Pandey A.K. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 4376-4380Crossref PubMed Scopus (722) Google showed that an M. tuberculosis yrbE4A disruption mutant is impaired in of of of of and growth with cholesterol as a In the we analysis and a direct of cholesterol uptake to the role of the Mce4 system of RHA1 in steroid also analysis to the role of Mce4 systems in jostii RHA1 was on a on T. R. J. Microbiol. PubMed Scopus Google plus either or of a steroid Cholesterol was from and were from was on the of protein by cells with and the protein with as the were and was as R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). was with the and was and gene expression were as R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). and sequences are in for and assays for and of for or for for A was for and genes of R. jostii RHA1 were the system as R. R. P. L. FEMS Microbiol. 2001; PubMed Scopus Google Scholar). of all are in and were to and a region of the genes of of the and the of into and were to the region of the genes. The of the first 20 including the of was cloned into A with with and was on the and the fragment was cloned into with and in for gene The deletion was by with and with sequences the genes. The gene deletion and the gene deletion were in the strains and respectively, as The genes were and The was with and and cloned in N. T. PubMed Scopus Google Scholar), Similarly, the and genes were and The was with and and into N. T. PubMed Scopus Google Scholar), The and were into the strain and the respectively, by A strain the genes was also by with Cholesterol uptake was in cell were to on and a cell of of in of were in and was from an of of cell were to the for a cell of of The were with for Cholesterol uptake was by the with of the cells on a the cells with of 20 and with of and with of The were in and in a to the of cholesterol by the cells. The of uptake was to be for than and was a uptake and cell a cell of of or was to cell to the of the were the and of A. Analysis of Scholar). The mce4 RHA1 mce4 the gene of mce loci and to be an operon (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar), mce4 loci in Mycobacterium Mycobacterium Mycobacterium and M. tuberculosis and also mce4 loci in M. M. de Mycobacterium Mycobacterium and Mycobacterium The mce4 gene of RHA1 have the to their in N. The genes of the RHA1 mce4 are of genes in mce4 The RHA1 mce4 the of two yrbE plus eight mce genes in all known mce4 However, the mce4 of RHA1 is in that is followed by two additional genes. The first of these is two of and a protein with an region similar to the of the of The of these a protein with to the of the of these genes to have in all of the but of is linked to mce4 The in are and respectively, are linked to the steroid metabolism gene of However, is of a that also the steroid metabolism genes and mce4 genes of S.L. M. S. Sidders B. R. A. Microbiol. 2007; PubMed Scopus (169) Google Scholar). The four genes of are in all of the and a a and two The gene of is in all the N. and an In the 11 genes from are with of 20 and with six of the predicted genes the following by four were of and but were the 11-gene mce4 of that This was further by including this of the were and all were including the on either of the 11-gene were also some of expression of the gene as a for expression of mce4 genes in an The gene was up-regulated 4.0-fold during growth on to during growth on pyruvate. Together, the suggest that the 11-gene mce4 is and as an The do the existence of additional the region including additional genes. mce4 that of RHA1 is to a gene encoding an However, the RHA1 genome two and encoding to the gene of M. tuberculosis. of these RHA1 genes are with mce loci of One or both of these function in the RHA1 Mce4 system. Growth of an deletion mutant of the genes in RHA1 the and deletion mutants R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar), the mutant the to on cholesterol two strains to that genes were the of the mutant The strain of the mutant with N. T. PubMed Scopus Google containing The strain the to on strain of the mutant with on this and the of the and deletion mutants to on is that the deletion have a expression of the genes. The and deletion mutants are also to have The strain of the mutant with N. T. PubMed Scopus Google containing but The strain also the to on This that the gene of the mce4 operon, is essential for growth on the that each of and one or more proteins essential for growth on Cholesterol role of the Mce4 system in cholesterol uptake was by cholesterol uptake by RHA1 and the mutant uptake of cholesterol by cell to cells were as cholesterol for be from the cells, to the and of cholesterol in the However, RHA1 cells on cholesterol uptake followed Michaelis-Menten kinetics and exhibited a low Km ± 0.1 for cholesterol was by of cells with the or either of two and that uptake is and more ATP-dependent The of in RHA1 is by studies N. PubMed Scopus Google Scholar, M.A. J. PubMed Scopus Google that have that of that are and to the consistent of these distinct that the The uptake for the cells was ± of but we predict a for cells. The and strains cholesterol uptake uptake phenotypes are consistent with the growth phenotypes of the Moreover, the and strains cholesterol uptake phenotypes are consistent with the growth but is that is more in the uptake The for this in of be the of cells for the uptake Thus, expression of the and genes from be for uptake but be for growth on indicate that of the mce4 genes are of a cholesterol uptake system. of RHA1 and the deletion mutants were for growth on a of and RHA1 was to on 5-α-cholestanol, and β-sitosterol, but on or The and mutants also the to on 5-α-cholestanol, and 5-α-cholestanol, and have similar The deletion mutants were in growth on and from the four in indicate that the Mce4 system 5-α-cholestanol, and One or more systems transport and but we the that the Mce4 system also the latter of mce4 with evidence that Mce4 systems are in steroid uptake in bacteria, we genome sequences with mce4 loci for linked steroid metabolism genes. for of the RHA1 gene, and gene genes of the in of A and of the steroid to although the gene in the genomes of RHA1 versus these genes were all in the region of the mce4 loci of both with the and operons in both R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). the we the genomes of M. M. M. M. M. M. M. and N. of all of the steroid metabolism genes were linked to the mce4 in each The encoded proteins than sequence to their RHA1 with the of and the Mce proteins are much than these with Mce proteins of RHA1 and The and operons were in all the Thus, in all genomes with mce4 loci are linked to steroid metabolism genes. This study the first direct evidence that an mce an uptake system that mce loci a of transporter S.M. Pandey A.K. Capite N. Fortune S.M. Rubin E.J. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 11760-11765Crossref PubMed Scopus (133) Google Scholar, N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar, S.L. M. S. Sidders B. R. A. Microbiol. 2007; PubMed Scopus (169) Google Scholar). This study further that the mce4 of RHA1 a system for steroid A.L. J. Biochem. PubMed Scopus Google Scholar), the Mce4 system of RHA1 is an transporter that this system 5-α-cholestanol, and of evidence indicate that all Mce4 systems function in steroid mce4 loci are with steroid metabolism genes in the genome of the known to have mce4 four have and to on M. Y. R. J. Microbiol. PubMed Scopus Google R. jostii R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar), M. R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar), and M. tuberculosis (10Pandey A.K. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 4376-4380Crossref PubMed Scopus (722) Google Scholar). the mce4 genes and cholesterol metabolism genes are in M. tuberculosis and M. S.L. M. S. Sidders B. R. A. Microbiol. 2007; PubMed Scopus (169) Google as as R. jostii R. T. Hara H. K. E. Davies J.E. L. Mohn W.W. Eltis L.D. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). additional Mycobacterium spp. on Y. R. J. Microbiol. PubMed Scopus Google Scholar). Thus, steroid metabolism and the Mce4 uptake system be nearly in the Mycobacterium, and be in such as Rhodococcus and are in in nearly all growth for include known and the of that the Mce4 system from Mce systems when the capacity to transport and with steroid metabolism genes. further that the Mce4 system was for a role in pathogenesis, for its in with In the and genes to be and as a 11-gene operon consistent with the that the mce1 operon of M. tuberculosis is as one A. M. V. Infect. Immun. 2003; PubMed Scopus Google Scholar). plus genes are during growth on further evidence for the role of the mce4 genes in steroid Analysis of M. tuberculosis and M. S.L. M. S. Sidders B. R. A. Microbiol. 2007; PubMed Scopus (169) Google that the mce4 operon of RHA1 be of a much that steroid metabolism genes and additional genes and that is by the of the mce4 operon, to be expression in RHA1 uptake was in cells. This is consistent with the of that we be for uptake systems cells with uptake might be to the of in their The evidence 11 proteins in a Mce4 steroid uptake system. include an two or and eight additional proteins of unknown function The for and genes for uptake and the growth phenotypes of all RHA1 deletion mutant strains indicate that a system in the of any of the of proteins. In although some Mce systems to the proteins are essential for a Mce4 system. do that all of the and Mce4 proteins are essential for steroid uptake but are consistent with this The of all and Mce4 proteins is also suggested by the of all genes in the mce4 loci of diverse actinobacteria (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar). is Mce systems so more proteins than do transporters. that the Mce proteins a complex that the role of proteins in bacterial uptake transporters. such a complex of the cell This function is consistent with the that these proteins are and in some to the (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google Scholar). This role might that proposed for bacterial cell to proteins are M. P. J. A. O. Science. 2003; PubMed Scopus Google Scholar). mce loci are in bacteria, such as members of Mycobacterium, Rhodococcus, and Nocardia, have cell I. 1998; PubMed Scopus Google Scholar). The is that mce loci are also in members of genes with to mce genes are also in some (15Casali N. Riley L.W. BMC Genomics. 2007; 8: 60Crossref PubMed Scopus (169) Google and O. P. C. E. J. PubMed Scopus Google Scholar). Thus, this of genes a of proteins in transport cell and the function of the Mce4 system to the role of Mce4 proteins in pathogenesis of M. tuberculosis, The studies of the M. tuberculosis mce4 of virulence in mice (8Sassetti C.M. Rubin E.J. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 12989-12994Crossref PubMed Scopus (1057) Google Scholar, 9Joshi S.M. Pandey A.K. Capite N. Fortune S.M. Rubin E.J. Sassetti C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 11760-11765Crossref PubMed Scopus (133) Google or of macrophage infection (11Rosas-Magallanes V. Stadthagen-Gomez G. Rauzier J. Barreiro L.B. Tailleux L. Boudou F. Griffin R. Nigou J. Jackson M. Gicquel B. Neyrolles O. Infect. Immun. 2007; 75: 504-507Crossref PubMed Scopus (57) Google Scholar). A for this is that steroid metabolism by M. tuberculosis is an of One is that host cell is is an growth for the bacterium some during infection, or Another is that of a steroid might the pathogen to its host. uptake of cholesterol be an the pathogen to and to the host is also that the of Mce4 proteins to cholesterol might play an role in pathogenesis by the the host or a from the host. with these was proposed that a of Mce4 proteins be in or bacterial interactions with host cells (4Mitra D. Saha B. Das D. Wiker H.G. Das A.K. Tuberculosis (Edinb.). 2005; 85: 337-345Crossref PubMed Scopus (13) Google Scholar). that Mce proteins an from the host (14Shimono N. Morici L. Casali N. Cantrell S. Sidders B. Ehrt S. Riley L.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 15918-15923Crossref PubMed Scopus (175) Google or facilitate host cell entry (1Arruda S. Bomfim G. Knights R. Huimabyron T. Riley L.W. Science. 1993; 261: 1454-1457Crossref PubMed Scopus (307) Google Scholar, S. Ehrt S. Kawamura I. Fujimura T. Shimono N. Anand N. Lu S. Cohen-Gould L. Riley L.W. Cell. Microbiol. 2001; 3: 247-254Crossref PubMed Scopus (131) Google be with of the Mce4 proteins by host cell cholesterol the of the are consistent with that the of cholesterol is essential for infection of host cells by C. L. Cell. Microbiol. 2006; 8: PubMed Scopus Google Scholar, J. J. Science. PubMed Scopus Google Scholar, P. C. I. J. Immunol. PubMed Scopus Google Scholar). the complex and virulence phenotypes of M. tuberculosis mce mutants, of Mce proteins are complex that Mce systems function in uptake and that the Mce4 system in steroid uptake that to of roles for the Mce proteins in pathogenesis of diverse actinobacteria, of is M. tuberculosis. of for in the of RHA1 gene deletion with

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