Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis
Summary Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcriptio...
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| Veröffentlicht in: | Molecular microbiology 2003-05, Vol.48 (3), p.833-843 |
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| container_title | Molecular microbiology |
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| creator | Park, Heui‐Dong Guinn, Kristi M. Harrell, Maria I. Liao, Reiling Voskuil, Martin I. Tompa, Martin Schoolnik, Gary K. Sherman, David R. |
| description | Summary
Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcription factor, Rv3133c/DosR. We performed targeted disruption of this locus followed by transcriptome analysis of wild‐type and mutant bacilli. Nearly all the genes powerfully regulated by hypoxia require Rv3133c/DosR for their induction. Computer analysis identified a consensus motif, a variant of which is located upstream of nearly all M. tuberculosis genes rapidly induced by hypoxia. Further, Rv3133c/DosR binds to the two copies of this motif upstream of the hypoxic response gene alpha‐crystallin. Mutations within the binding sites abolish both Rv3133c/DosR binding as well as hypoxic induction of a downstream reporter gene. Also, mutation experiments with Rv3133c/DosR confirmed sequence‐based predictions that the C‐terminus is responsible for DNA binding and that the aspartate at position 54 is essential for function. Together, these results demonstrate that Rv3133c/DosR is a transcription factor of the two‐component response regulator class, and that it is the primary mediator of a hypoxic signal within M. tuberculosis. |
| doi_str_mv | 10.1046/j.1365-2958.2003.03474.x |
| format | Article |
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Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcription factor, Rv3133c/DosR. We performed targeted disruption of this locus followed by transcriptome analysis of wild‐type and mutant bacilli. Nearly all the genes powerfully regulated by hypoxia require Rv3133c/DosR for their induction. Computer analysis identified a consensus motif, a variant of which is located upstream of nearly all M. tuberculosis genes rapidly induced by hypoxia. Further, Rv3133c/DosR binds to the two copies of this motif upstream of the hypoxic response gene alpha‐crystallin. Mutations within the binding sites abolish both Rv3133c/DosR binding as well as hypoxic induction of a downstream reporter gene. Also, mutation experiments with Rv3133c/DosR confirmed sequence‐based predictions that the C‐terminus is responsible for DNA binding and that the aspartate at position 54 is essential for function. Together, these results demonstrate that Rv3133c/DosR is a transcription factor of the two‐component response regulator class, and that it is the primary mediator of a hypoxic signal within M. tuberculosis.</description><identifier>ISSN: 0950-382X</identifier><identifier>EISSN: 1365-2958</identifier><identifier>DOI: 10.1046/j.1365-2958.2003.03474.x</identifier><identifier>PMID: 12694625</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Aspartic Acid - metabolism ; Bacteria ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Binding sites ; Gene Expression Regulation, Bacterial ; Gene loci ; Gene Targeting ; Genes, Reporter ; Humans ; Hypoxia - metabolism ; Microbiology ; Mutation ; Mycobacterium tuberculosis - genetics ; Mycobacterium tuberculosis - metabolism ; Oligonucleotide Array Sequence Analysis ; Oxygen - metabolism ; Protein Binding ; Regulatory Sequences, Nucleic Acid ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tuberculosis ; Tuberculosis - metabolism</subject><ispartof>Molecular microbiology, 2003-05, Vol.48 (3), p.833-843</ispartof><rights>Copyright Blackwell Publishing May 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5284-3519654a392dd17e6e7200ef53cfc9a4fc5e54bede0b823349efc10cc6d217a83</citedby><cites>FETCH-LOGICAL-c5284-3519654a392dd17e6e7200ef53cfc9a4fc5e54bede0b823349efc10cc6d217a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1365-2958.2003.03474.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1365-2958.2003.03474.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12694625$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Heui‐Dong</creatorcontrib><creatorcontrib>Guinn, Kristi M.</creatorcontrib><creatorcontrib>Harrell, Maria I.</creatorcontrib><creatorcontrib>Liao, Reiling</creatorcontrib><creatorcontrib>Voskuil, Martin I.</creatorcontrib><creatorcontrib>Tompa, Martin</creatorcontrib><creatorcontrib>Schoolnik, Gary K.</creatorcontrib><creatorcontrib>Sherman, David R.</creatorcontrib><title>Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis</title><title>Molecular microbiology</title><addtitle>Mol Microbiol</addtitle><description>Summary
Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcription factor, Rv3133c/DosR. We performed targeted disruption of this locus followed by transcriptome analysis of wild‐type and mutant bacilli. Nearly all the genes powerfully regulated by hypoxia require Rv3133c/DosR for their induction. Computer analysis identified a consensus motif, a variant of which is located upstream of nearly all M. tuberculosis genes rapidly induced by hypoxia. Further, Rv3133c/DosR binds to the two copies of this motif upstream of the hypoxic response gene alpha‐crystallin. Mutations within the binding sites abolish both Rv3133c/DosR binding as well as hypoxic induction of a downstream reporter gene. Also, mutation experiments with Rv3133c/DosR confirmed sequence‐based predictions that the C‐terminus is responsible for DNA binding and that the aspartate at position 54 is essential for function. Together, these results demonstrate that Rv3133c/DosR is a transcription factor of the two‐component response regulator class, and that it is the primary mediator of a hypoxic signal within M. tuberculosis.</description><subject>Aspartic Acid - metabolism</subject><subject>Bacteria</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Binding sites</subject><subject>Gene Expression Regulation, Bacterial</subject><subject>Gene loci</subject><subject>Gene Targeting</subject><subject>Genes, Reporter</subject><subject>Humans</subject><subject>Hypoxia - metabolism</subject><subject>Microbiology</subject><subject>Mutation</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Mycobacterium tuberculosis - metabolism</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Oxygen - metabolism</subject><subject>Protein Binding</subject><subject>Regulatory Sequences, Nucleic Acid</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tuberculosis</subject><subject>Tuberculosis - metabolism</subject><issn>0950-382X</issn><issn>1365-2958</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtv1DAUhS0EokPhLyCLBbukfidegIQqHpU6QqpAYmc5zk3Ho0wc7KSd-fc4zKg8NrCyrfudo3t8EMKUlJQIdbEtKVeyYFrWJSOEl4SLSpT7R2j1MHiMVkRLUvCafTtDz1LaEkI5UfwpOqNMaaGYXKHbmztOOXcXbUg32Cds8RTtkFz04-TDgDvrphDxtLET3kHr7QQpvwBvDmPYe4cjpDEMCXDo8PrgQpMFEP28w9PcQHRzH5JPz9GTzvYJXpzOc_T1w_svl5-K688fry7fXRdOsloUXFKtpLBcs7alFSiocj7oJHed01Z0ToIUDbRAmppxLjR0jhLnVMtoZWt-jt4efce5yes6GHKc3ozR72w8mGC9-XMy-I25DXeGas0kVdng9ckghu8zpMnsfHLQ93aAMCdTcVoLpek_QVpXSmmtM_jqL3Ab5jjkXzBLWFJLsbjVR8jFkFKE7mFlSszSudmapVqzVGuWzs3Pzs0-S1_-HvmX8FRyBt4cgXvfw-G_jc16fbXc-A9hzbzH</recordid><startdate>200305</startdate><enddate>200305</enddate><creator>Park, Heui‐Dong</creator><creator>Guinn, Kristi M.</creator><creator>Harrell, Maria I.</creator><creator>Liao, Reiling</creator><creator>Voskuil, Martin I.</creator><creator>Tompa, Martin</creator><creator>Schoolnik, Gary K.</creator><creator>Sherman, David R.</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200305</creationdate><title>Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis</title><author>Park, Heui‐Dong ; Guinn, Kristi M. ; Harrell, Maria I. ; Liao, Reiling ; Voskuil, Martin I. ; Tompa, Martin ; Schoolnik, Gary K. ; Sherman, David R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5284-3519654a392dd17e6e7200ef53cfc9a4fc5e54bede0b823349efc10cc6d217a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Aspartic Acid - metabolism</topic><topic>Bacteria</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - metabolism</topic><topic>Binding sites</topic><topic>Gene Expression Regulation, Bacterial</topic><topic>Gene loci</topic><topic>Gene Targeting</topic><topic>Genes, Reporter</topic><topic>Humans</topic><topic>Hypoxia - metabolism</topic><topic>Microbiology</topic><topic>Mutation</topic><topic>Mycobacterium tuberculosis - genetics</topic><topic>Mycobacterium tuberculosis - metabolism</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Oxygen - metabolism</topic><topic>Protein Binding</topic><topic>Regulatory Sequences, Nucleic Acid</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tuberculosis</topic><topic>Tuberculosis - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, Heui‐Dong</creatorcontrib><creatorcontrib>Guinn, Kristi M.</creatorcontrib><creatorcontrib>Harrell, Maria I.</creatorcontrib><creatorcontrib>Liao, Reiling</creatorcontrib><creatorcontrib>Voskuil, Martin I.</creatorcontrib><creatorcontrib>Tompa, Martin</creatorcontrib><creatorcontrib>Schoolnik, Gary K.</creatorcontrib><creatorcontrib>Sherman, David R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular microbiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Heui‐Dong</au><au>Guinn, Kristi M.</au><au>Harrell, Maria I.</au><au>Liao, Reiling</au><au>Voskuil, Martin I.</au><au>Tompa, Martin</au><au>Schoolnik, Gary K.</au><au>Sherman, David R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis</atitle><jtitle>Molecular microbiology</jtitle><addtitle>Mol Microbiol</addtitle><date>2003-05</date><risdate>2003</risdate><volume>48</volume><issue>3</issue><spage>833</spage><epage>843</epage><pages>833-843</pages><issn>0950-382X</issn><eissn>1365-2958</eissn><abstract>Summary
Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcription factor, Rv3133c/DosR. We performed targeted disruption of this locus followed by transcriptome analysis of wild‐type and mutant bacilli. Nearly all the genes powerfully regulated by hypoxia require Rv3133c/DosR for their induction. Computer analysis identified a consensus motif, a variant of which is located upstream of nearly all M. tuberculosis genes rapidly induced by hypoxia. Further, Rv3133c/DosR binds to the two copies of this motif upstream of the hypoxic response gene alpha‐crystallin. Mutations within the binding sites abolish both Rv3133c/DosR binding as well as hypoxic induction of a downstream reporter gene. Also, mutation experiments with Rv3133c/DosR confirmed sequence‐based predictions that the C‐terminus is responsible for DNA binding and that the aspartate at position 54 is essential for function. Together, these results demonstrate that Rv3133c/DosR is a transcription factor of the two‐component response regulator class, and that it is the primary mediator of a hypoxic signal within M. tuberculosis.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>12694625</pmid><doi>10.1046/j.1365-2958.2003.03474.x</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular microbiology, 2003-05, Vol.48 (3), p.833-843 |
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| subjects | Aspartic Acid - metabolism Bacteria Bacterial Proteins - genetics Bacterial Proteins - metabolism Binding sites Gene Expression Regulation, Bacterial Gene loci Gene Targeting Genes, Reporter Humans Hypoxia - metabolism Microbiology Mutation Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - metabolism Oligonucleotide Array Sequence Analysis Oxygen - metabolism Protein Binding Regulatory Sequences, Nucleic Acid Transcription Factors - genetics Transcription Factors - metabolism Tuberculosis Tuberculosis - metabolism |
| title | Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis |
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