Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence
ABSTRACT Many bacteria metabolize ethanolamine as a nutrient source through cytoplasmic organelles named bacterial microcompartments (BMCs). Here we investigated the molecular assembly, regulation, and function of BMCs in Fusobacterium nucleatum—a Gram-negative oral pathobiont that is associated wit...
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American Society for Microbiology
2025-02-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03405-24 |
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| author | Dana S. Franklin Yi-Wei Chen Yimin Chen Manuel Wittchen Angela Agnew Alexis Luu Julian P. Whitelegge Z. Hong Zhou Andreas Tauch Asis Das Hung Ton-That |
| author_facet | Dana S. Franklin Yi-Wei Chen Yimin Chen Manuel Wittchen Angela Agnew Alexis Luu Julian P. Whitelegge Z. Hong Zhou Andreas Tauch Asis Das Hung Ton-That |
| author_sort | Dana S. Franklin |
| collection | DOAJ |
| description | ABSTRACT Many bacteria metabolize ethanolamine as a nutrient source through cytoplasmic organelles named bacterial microcompartments (BMCs). Here we investigated the molecular assembly, regulation, and function of BMCs in Fusobacterium nucleatum—a Gram-negative oral pathobiont that is associated with adverse pregnancy outcomes. The F. nucleatum genome harbors a conserved ethanolamine utilization (eut) locus with 21 genes that encode several putative BMC shell proteins and a two-component signal transduction system (TCS), in addition to the enzymes for ethanolamine transport and catabolism. We show that the expression of most of these genes and BMC formation are highly increased in wild-type fusobacteria when cultured in the presence of ethanolamine as a nutrient source. Deletion of the response regulator EutV eliminated this induction of eut mRNAs and BMCs, thus demonstrating that BMC formation is transcriptionally regulated by the TCS EutV-EutW in response to ethanolamine. Mass spectrometry of isolated BMCs unveiled the identity of the constituent proteins EutL, EutM1, EutM2, and EutN. Consistent with the role of these proteins in BMC assembly and metabolism, deletion of eutN, eutL/eutM1/eutM2, or eutL/eutM1/eutM2/eutN not only affected BMC formation but also ethanolamine utilization, causing cell growth defects with ethanolamine as a nutrient. BMCs are also assembled in fusobacteria cultured with placental cells or the culture media, a process that is dependent on the BMC shell proteins. Significantly, we show that the eutN mutant is defective in inducing preterm birth in a mouse model. Together, these results establish that the BMC-mediated metabolism of ethanolamine is critical for fusobacterial virulence.IMPORTANCEThe oral anaerobe Fusobacterium nucleatum can spread to distal internal organs, such as the colon and placenta, thereby promoting the development of colorectal cancer and inducing preterm birth, respectively. Yet, how this opportunistic pathogen adapts to the various metabolically distinct host cellular niches remains poorly understood. We demonstrated here that this microbe assembles specialized metabolic organelles, termed bacterial microcompartments (BMCs), to utilize environmental ethanolamine (EA) as a key environmental nutrient source. The formation of F. nucleatum BMCs, containing BMC shell proteins EutLM1M2N, is controlled by a two-component system, EutV-EutW, responsive to EA. Significantly, this ability of F. nucleatum to form BMCs in response to EA is crucial for its pathogenicity evidenced by the fact that the genetic disruption of BMC formation reduces fusobacterial virulence in a mouse model of preterm birth. |
| format | Article |
| id | doaj-art-f805d0d24e9d4c86a41b9a88663da99d |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-f805d0d24e9d4c86a41b9a88663da99d2025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03405-24Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulenceDana S. Franklin0Yi-Wei Chen1Yimin Chen2Manuel Wittchen3Angela Agnew4Alexis Luu5Julian P. Whitelegge6Z. Hong Zhou7Andreas Tauch8Asis Das9Hung Ton-That10Molecular Biology Institute, University of California, Los Angeles, California, USADivision of Oral & Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, California, USADivision of Oral & Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, California, USACenter for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, GermanyDepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USADivision of Oral & Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, California, USAPasarow Mass Spectrometry Laboratory, NPI-Semel Institute, University of California Los Angeles, Los Angeles, California, USADepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USACenter for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, GermanyDepartment of Medicine, Neag Comprehensive Cancer Center, School of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USAMolecular Biology Institute, University of California, Los Angeles, California, USAABSTRACT Many bacteria metabolize ethanolamine as a nutrient source through cytoplasmic organelles named bacterial microcompartments (BMCs). Here we investigated the molecular assembly, regulation, and function of BMCs in Fusobacterium nucleatum—a Gram-negative oral pathobiont that is associated with adverse pregnancy outcomes. The F. nucleatum genome harbors a conserved ethanolamine utilization (eut) locus with 21 genes that encode several putative BMC shell proteins and a two-component signal transduction system (TCS), in addition to the enzymes for ethanolamine transport and catabolism. We show that the expression of most of these genes and BMC formation are highly increased in wild-type fusobacteria when cultured in the presence of ethanolamine as a nutrient source. Deletion of the response regulator EutV eliminated this induction of eut mRNAs and BMCs, thus demonstrating that BMC formation is transcriptionally regulated by the TCS EutV-EutW in response to ethanolamine. Mass spectrometry of isolated BMCs unveiled the identity of the constituent proteins EutL, EutM1, EutM2, and EutN. Consistent with the role of these proteins in BMC assembly and metabolism, deletion of eutN, eutL/eutM1/eutM2, or eutL/eutM1/eutM2/eutN not only affected BMC formation but also ethanolamine utilization, causing cell growth defects with ethanolamine as a nutrient. BMCs are also assembled in fusobacteria cultured with placental cells or the culture media, a process that is dependent on the BMC shell proteins. Significantly, we show that the eutN mutant is defective in inducing preterm birth in a mouse model. Together, these results establish that the BMC-mediated metabolism of ethanolamine is critical for fusobacterial virulence.IMPORTANCEThe oral anaerobe Fusobacterium nucleatum can spread to distal internal organs, such as the colon and placenta, thereby promoting the development of colorectal cancer and inducing preterm birth, respectively. Yet, how this opportunistic pathogen adapts to the various metabolically distinct host cellular niches remains poorly understood. We demonstrated here that this microbe assembles specialized metabolic organelles, termed bacterial microcompartments (BMCs), to utilize environmental ethanolamine (EA) as a key environmental nutrient source. The formation of F. nucleatum BMCs, containing BMC shell proteins EutLM1M2N, is controlled by a two-component system, EutV-EutW, responsive to EA. Significantly, this ability of F. nucleatum to form BMCs in response to EA is crucial for its pathogenicity evidenced by the fact that the genetic disruption of BMC formation reduces fusobacterial virulence in a mouse model of preterm birth.https://journals.asm.org/doi/10.1128/mbio.03405-24Fusobacterium nucleatumbacterial microcompartmentethanolamine utilizationpreterm birthelectron microscopy |
| spellingShingle | Dana S. Franklin Yi-Wei Chen Yimin Chen Manuel Wittchen Angela Agnew Alexis Luu Julian P. Whitelegge Z. Hong Zhou Andreas Tauch Asis Das Hung Ton-That Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence mBio Fusobacterium nucleatum bacterial microcompartment ethanolamine utilization preterm birth electron microscopy |
| title | Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence |
| title_full | Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence |
| title_fullStr | Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence |
| title_full_unstemmed | Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence |
| title_short | Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence |
| title_sort | ethanolamine induced assembly of microcompartments is required for fusobacterium nucleatum virulence |
| topic | Fusobacterium nucleatum bacterial microcompartment ethanolamine utilization preterm birth electron microscopy |
| url | https://journals.asm.org/doi/10.1128/mbio.03405-24 |
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