Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces*

  1. Yin-Hua Lu (芦 银华)‡,**4
  1. From the ‡Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032,
  2. the §University of Chinese Academy of Sciences, Beijing 100049,
  3. the College of Veterinary Medicine, Yangzhou University, Yangzhou 225009,
  4. the ‖Jiangsu National Synergetic Innovation Center for Advanced Materials, SICAM, Nanjing 210009, and
  5. the **Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China
  1. ↵2 To whom correspondence may be addressed. Tel.: 86-0514-87972590; E-mail: yzgqzhu{at}yzu.edu.cn.
  2. ↵3 To whom correspondence may be addressed. Tel.: 86-21-54924172; Fax: 86-21-54924015; E-mail: whjiang{at}sibs.ac.cn.
  3. ↵4 To whom correspondence may be addressed. Tel.: 86-21-54924178; Fax: 86-21-54924015; E-mail: yhlu{at}sibs.ac.cn.

  1. ↵1 Both authors contributed equally to this work.

  2. Edited by Joel Gottesfeld

Abstract

GlnR, an OmpR-like orphan two-component system response regulator, is a master regulator of nitrogen metabolism in the genus Streptomyces. In this work, evidence that GlnR is also directly involved in the regulation of antibiotic biosynthesis is provided. In the model strain Streptomyces coelicolor M145, an in-frame deletion of glnR resulted in markedly increased actinorhodin (ACT) production but reduced undecylprodigiosin (RED) biosynthesis when exposed to R2YE culture medium. Transcriptional analysis coupled with DNA binding studies revealed that GlnR represses ACT but activates RED production directly via the pathway-specific activator genes actII-ORF4 and redZ, respectively. The precise GlnR-binding sites upstream of these two target genes were defined. In addition, the direct involvement of GlnR in antibiotic biosynthesis was further identified in Streptomyces avermitilis, which produces the important anthelmintic agent avermectin. We found that S. avermitilis GlnR (GlnRsav) could stimulate avermectin but repress oligomycin production directly through the respective pathway-specific activator genes, aveR and olmRI/RII. To the best of our knowledge, this report describes the first experimental evidence demonstrating that GlnR regulates antibiotic biosynthesis directly through pathway-specific regulators in Streptomyces. Our results suggest that GlnR-mediated regulation of antibiotic biosynthesis is likely to be universal in streptomycetes. These findings also indicate that GlnR is not only a master nitrogen regulator but also an important controller of secondary metabolism, which may help to balance nitrogen metabolism and antibiotic biosynthesis in streptomycetes.

Footnotes

  • ↵* This work was supported by National Natural Science Foundation of China Grants 31630003, 31421061, 31370081, and 31570072. The authors declare that they have no conflicts of interest with the contents of this article.

  • ↵Graphic This article contains supplemental Table S1 and Figs. S1 and S2.

  • Received October 7, 2016.
  • Revision received November 3, 2016.
View this article with LENS
Table of Contents

This Article

  1. First Published on November 8, 2016 doi: 10.1074/jbc.M116.762476 The Journal of Biological Chemistry 291, 26443-26454.
  1. » Abstract(Free)
  2. Full Text
  3. PDF
  4. Supplemental Data
  5. All Versions of this Article:
    1. M116.762476v1
    2. 291/51/26443 (most recent)

Classifications

Article Usage Stats

  1. Article Usage Statistics

Submit your work to JBC.

You'll be in good company.