Dissection of the molecular circuitry controlling virulence in Francisella tularensis
- Duke Univ., School of Medicine, Durham, NC (United States). Dept. of Biochemistry
- Univ. of Wisconsin, Madison, WI (United States). Dept. of Bacteriology
- Harvard Medical School, Boston, MA (United States). Division of Infectious Diseases, Boston Children’s Hospital
Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators—the heteromeric macrophage growth locus protein A (MglA)–stringent starvation protein A (SspA) complex and the DNA-binding protein pathogenicity island gene regulator (PigR)—activates FPI transcription and thus is essential for virulence. Intriguingly, the second messenger, guanosine–tetraphosphate (ppGpp), which is produced during infection, is also involved in coordinating Francisella virulence; however, its role has been unclear. Here we identify MglA–SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA–SspA. We demonstrate that MglA–SspA, which binds RNA polymerase (RNAP), also interacts with the C-terminal domain of PigR, thus anchoring the (MglA–SspA)–RNAP complex to the FPI promoter. Furthermore, we show that MglA–SspA must be bound to ppGpp to mediate high-affinity interactions with PigR. Thus, these studies unveil a novel pathway different from those described previously for regulation of transcription by ppGpp. The data also indicate that F. tularensis pathogenesis is controlled by a highly interconnected molecular circuitry in which the virulence machinery directly senses infection via a small molecule stress signal.
- Research Organization:
- Univ. of California, Oakland, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Howard Hughes Medical Institute
- Grant/Contract Number:
- AC02-05CH11231; GM115547; GM37048; AI081693
- OSTI ID:
- 1625616
- Journal Information:
- Genes & Development, Vol. 31, Issue 15; ISSN 0890-9369
- Publisher:
- Cold Springs Harbor Laboratory PressCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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