Skip to main content
SpringerLink
Log in

An extracytoplasmic function sigma factor, σ25, differentially regulates avermectin and oligomycin biosynthesis in Streptomyces avermitilis

  • Applied genetics and molecular biotechnology
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

σ25 is an extracytoplasmic function (ECF) σ factor in the bacterium Streptomyces avermitilis that plays a differential regulatory role in avermectin and oligomycin biosynthesis. Gene deletion, complementation, and overexpression experiments showed that σ25 inhibited avermectin production but promoted oligomycin production. σ25 indirectly inhibited avermectin production by affecting the transcription of the pathway-specific activator gene aveR, whereas it directly activated oligomycin production by initiating transcription of the pathway-specific activator gene olmRI. The divergently transcribed genes smrAB are located upstream of sig25 and encode a putative two-component system (TCS). σ25 was found to initiate its own transcription, and its expression was directly activated by SmrA. The precise SmrA-binding sites in the region upstream of sig25 were determined by DNase I footprinting assays and identified two direct repeat sequences CTGTGA-n5-CTGTGA, suggesting that SmrA regulates sig25 transcription by binding to these direct repeats. The deletion of smrAB had the similar effect on avermectin and oligomycin A production to the deletion of sig25, indicating that σ25 and SmrAB function similarly in the regulation of antibiotic production. These findings helpfully clarify the regulation of antibiotic biosynthesis by an ECF σ factor-TCS signal transduction system in S. avermitilis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147

    Article  PubMed  Google Scholar 

  • Bierman M, Logan R, O'Brien K, Seno ET, Rao RN, Schoner BE (1992) Plasmid cloning vectors for the conjugal transfer of DNA from Escherichia coli to Streptomyces spp. Gene 116:43–49

    Article  CAS  PubMed  Google Scholar 

  • Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R, Kong YL, Monaghan RL, Olson G, Putter I, Tunac JB, Wallick H, Stapley EO, Oiwa R, Omura S (1979) Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob Agents Chemother 15:361–367

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cao M, Wang T, Ye R, Helmann JD (2002) Antibiotics that inhibit cell wall biosynthesis induce expression of the Bacillus subtilis sigma (W) and sigma (M) regulons. Mol Microbiol 45:1267–1276

    Article  CAS  PubMed  Google Scholar 

  • Chaba R, Alba BM, Guo MS, Sohn J, Ahuja N, Sauer RT, Gross CA (2011) Signal integration by DegS and RseB governs the σE-mediated envelope stress response in Escherichia coli. Proc Natl Acad Sci U S A 108:2106–2111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen Z, Wen J, Song Y, Wen Y, Li JL (2007) Enhancement and selective production of avermectin B by recombinants of Streptomyces avermitilis via intraspecific protoplast fusion. Chin Sci Bull 52:616–622

    Article  CAS  Google Scholar 

  • Francez-Charlot A, Frunzke J, Reichen C, Ebneter JZ, Gourion B, Vorholt JA (2009) Sigma factor mimicry involved in regulation of general stress response. Proc Natl Acad Sci U S A 106:3467–3472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Guo J, Zhao JL, Li LL, Chen Z, Wen Y, Li JL (2010) The pathway-specific regulator AveR from Streptomyces avermitilis positively regulates avermectin production while it negatively affects oligomycin biosynthesis. Mol Genet Genomics 283:123–133

    Article  CAS  PubMed  Google Scholar 

  • Guo J, Zhang X, Luo S, He F, Chen Z, Wen Y, Li JL (2013) A novel TetR family transcriptional regulator, SAV576, negatively controls avermectin biosynthesis in Streptomyces avermitilis. PLoS One 8:e71330

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hong HJ, Paget MS, Buttner MJ (2002) A signal transduction system in Streptomyces coelicolor that activates the expression of a putative cell wall glycan operon in response to vancomycin and other cell wall-specific antibiotics. Mol Microbiol 44:1199–1211

    Article  CAS  PubMed  Google Scholar 

  • Hutchings MI, Hong HJ, Leibovitz E, Sutcliffe IC, Buttner MJ (2006) The sigma (E) cell envelope stress response of Streptomyces coelicolor is influenced by a novel lipoprotein, CseA. J Bacteriol 188:7222–7229

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ikeda H, Kotaki H, Tanaka H, Omura S (1988) Involvement of glucose catabolism in avermectin production by Streptomyces avermitilis. Antimicrob Agents Chemother 32:282–284

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531

    Article  PubMed  Google Scholar 

  • Jiang LB, Liu YP, Wang P, Wen Y, Song Y, Chen Z, Li JL (2011) Inactivation of the extracytoplasmic function sigma factor Sig6 stimulates avermectin production in Streptomyces avermitilis. Biotechnol Lett 33:1955–1961

    Article  CAS  PubMed  Google Scholar 

  • Kieser T, Bibb MJ, Buttner MJ, Chater KF, Hopwood DA (2000) Practical Streptomyces genetics: a laboratory manual. John Innes Foundation, Norwich

    Google Scholar 

  • Kitani S, Ikeda H, Sakamoto T, Noguchi S, Nihira T (2009) Characterization of a regulatory gene, aveR, for the biosynthesis of avermectin in Streptomyces avermitilis. Appl Microbiol Biotechnol 82:1089–1096

    Article  CAS  PubMed  Google Scholar 

  • Li W, Stevenson CE, Burton N, Jakimowicz P, Paget MS, Buttner MJ, Lawson DM, Kleanthous C (2002) Identification and structure of the anti-sigma factor-binding domain of the disulphide-stress regulated sigma factor σR from Streptomyces coelicolor. J Mol Biol 323:225–236

    Article  CAS  PubMed  Google Scholar 

  • Li LL, Guo J, Wen Y, Chen Z, Song Y, Li JL (2010) Overexpression of ribosome recycling factor causes increased production of avermectin in Streptomyces avermitilis strains. J Ind Microbiol Biotechnol 37:673–679

    Article  CAS  PubMed  Google Scholar 

  • Lin XP, Wen Y, Li M, Chen Z, Guo J, Song Y, Li JL (2009) A new strain of Streptomyces avermitilis produces high yield of oligomycin A with potent anti-tumor activity on human cancer cell lines in vitro. Appl Microbiol Biotechnol 81:839–845

    Article  CAS  PubMed  Google Scholar 

  • Macneil DJ, Klapko LM (1987) Transformation of Streptomyces avermitilis by plasmid DNA. J Ind Microbiol 2:209–218

    Article  CAS  Google Scholar 

  • Mascher T (2013) Signaling diversity and evolution of extracytoplasmic function (ECF) σ factors. Curr Opin Microbiol 16:148–155

    Article  CAS  PubMed  Google Scholar 

  • Meng XD, Michael HB, Scot AW (2005) A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors. Nat Biotechnol 23:988–994

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Omura S, Ikeda H, Ishikawa J, Hanamoto A, Takahashi C, Shinose M, Takahashi Y, Horikawa H, Nakazawa H, Osonoe T, Kikuchi H, Shiba T, Sakaki Y, Hattori M (2001) Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci U S A 98:12215–12220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paget MSB, Chamberlin L, Atrih A, Foster SJ, Buttner MJ (1999) Evidence that the extracytoplasmic function sigma factor σE is required for normal cell wall structure in Streptomyces coelicolor A3(2). J Bacteriol 181:204–211

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pinna LA, Lorini M, Moret V, Siliprandi N (1967) Effect of oligomycin and succinate on mitochondrial metabolism of adenine nucleotides. Biochim Biophys Acta 143:18–25

    Article  CAS  PubMed  Google Scholar 

  • Sambrook J, MacCallum P, and Russell D (2001) Molecular cloning: a laboratory manual, third ed. Cold Spring Harbor Laboratory Press

  • Shu D, Chen L, Wang W, Yu Z, Ren C, Zhang W, Yang S, Lu Y, Jiang W (2009) afsQ1-Q2-sigQ is a pleiotropic but conditionally required signal transduction system for both secondary metabolism and morphological development in Streptomyces coelicolor. Appl Microbiol Biotechnol 81:1149–1160

    Article  CAS  PubMed  Google Scholar 

  • Staron A, Sofia HJ, Dietrich S, Ulrich LE, Liesegang H, Mascher T (2009) The third pillar of bacterial signal transduction: classification of the extracytoplasmic function (ECF) sigma factor protein family. Mol Microbiol 74:557–581

    Article  CAS  PubMed  Google Scholar 

  • Tiffert Y, Supra P, Wurm R, Wohlleben W, Wagner R, Reuther J (2008) The Streptomyces coelicolor GlnR regulon: identification of new GlnR targets and evidence for a central role of GlnR in nitrogen metabolism in actinomycetes. Mol Microbiol 67:861–880

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Mast Y, Wang J, Zhang W, Zhao G, Wohlleben W, Lu Y, Jiang W (2013) Identification of two-component system AfsQ1/Q2 regulon and its cross-regulation with GlnR in Streptomyces coelicolor. Mol Microbiol 87:30–48

    Article  CAS  PubMed  Google Scholar 

  • Yu Q, Bai LQ, Zhou XF, Deng ZX (2012) Inactivation of the positive LuxR-type oligomycin biosynthesis regulators OlmRI and OlmRII increases avermectin production in Streptomyces avermitilis. Chin Sci Bull 8:869–876

    Article  Google Scholar 

  • Zhao JL, Wen Y, Chen Z, Song Y, Li JL (2007) An adpA homologue in Streptomyces avermitilis is involved in regulation of morphogenesis and melanogenesis. Chin Sci Bull 52:623–630

    Article  CAS  Google Scholar 

  • Zhuo Y, Zhang W, Chen D, Gao H, Tao J, Liu M, Gou Z, Zhou X, Ye BC, Zhang Q, Zhang S, Zhang LX (2010) Reverse biological engineering of hrdB to enhance the production of avermectins in an industrial strain of Streptomyces avermitilis. Proc Natl Acad Sci U S A 107:11250–11254

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zianni M, Tessanne K, Merighi M, Laguna R, Tabita FR (2006) Identification of the DNA bases of a DNase I footprint by the use of dye primer sequencing on an automated capillary DNA analysis instrument. J Biomol Tech 17:103–113

    PubMed Central  PubMed  Google Scholar 

  • Zweers JC, Nicolas P, Wiegert T, van Dijl JM, Denham EL (2012) Definition of the σ (W) regulon of Bacillus subtilis in the absence of stress. PLoS One 7:e48471

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (grant no. 31170045). The authors are grateful to Dr. S. Anderson (Pacific Northwest Diabetes Research Institute, Seattle, WA, USA) for English editing of the manuscript.

Author information

Authors and Affiliations

  1. State Key Laboratory of Agro-Biotechnology and MOA Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing, 100193, People’s Republic of China

    Shuai Luo, Di Sun, Jianya Zhu, Zhi Chen, Ying Wen & Jilun Li

Authors
  1. Shuai Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Di Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianya Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jilun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ying Wen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 347 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, S., Sun, D., Zhu, J. et al. An extracytoplasmic function sigma factor, σ25, differentially regulates avermectin and oligomycin biosynthesis in Streptomyces avermitilis . Appl Microbiol Biotechnol 98, 7097–7112 (2014). https://doi.org/10.1007/s00253-014-5759-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-014-5759-7

Keywords

Search

Navigation