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Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity

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Abstract
During microbial infection, proteins are modified by the ubiquitin-like protein ISG15. Here, the authors uncover RNF213 as a sensor for ISGylated proteins on the surface of lipid droplets, showing that RNF213 has antiviral properties but also directly targets intracellular bacteria in infected cells. ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.
Keywords
INTERFERON-STIMULATED GENE, PAPAIN-LIKE PROTEASE, LISTERIA-MONOCYTOGENES, MOYAMOYA-DISEASE, HUMAN INTERACTOME, MYCOBACTERIUM-TUBERCULOSIS, ISG15, LIGASE, VIRUS, AUTOPHAGY

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MLA
Thery, Fabien Henri, et al. “Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity.” NATURE COMMUNICATIONS, vol. 12, no. 1, 2021, doi:10.1038/s41467-021-26061-w.
APA
Thery, F. H., Martina, L., Asselman, C., Repo, H., Zhang, Y., Sedeyn, K., … Impens, F. (2021). Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity. NATURE COMMUNICATIONS, 12(1). https://doi.org/10.1038/s41467-021-26061-w
Chicago author-date
Thery, Fabien Henri, Lia Martina, Caroline Asselman, Heidi Repo, Y Zhang, Koen Sedeyn, Georgios Moschonas, et al. 2021. “Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity.” NATURE COMMUNICATIONS 12 (1). https://doi.org/10.1038/s41467-021-26061-w.
Chicago author-date (all authors)
Thery, Fabien Henri, Lia Martina, Caroline Asselman, Heidi Repo, Y Zhang, Koen Sedeyn, Georgios Moschonas, C Bredow, QW Teo, J Zhang, M Vessely, Kevin Leandro, Denzel Eggermont, Delphine De Sutter, Katie Boucher, Tino Hochepied, Nele Festjens, Nico Callewaert, Xavier Saelens, Bart Dermaut, KP Knobeloch, A Beling, S Sanyal, L Radoshevich, Sven Eyckerman, and Francis Impens. 2021. “Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity.” NATURE COMMUNICATIONS 12 (1). doi:10.1038/s41467-021-26061-w.
Vancouver
1.
Thery FH, Martina L, Asselman C, Repo H, Zhang Y, Sedeyn K, et al. Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity. NATURE COMMUNICATIONS. 2021;12(1).
IEEE
[1]
F. H. Thery et al., “Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity,” NATURE COMMUNICATIONS, vol. 12, no. 1, 2021.
@article{8722778,
  abstract     = {{During microbial infection, proteins are modified by the ubiquitin-like protein ISG15. Here, the authors uncover RNF213 as a sensor for ISGylated proteins on the surface of lipid droplets, showing that RNF213 has antiviral properties but also directly targets intracellular bacteria in infected cells.

ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.}},
  articleno    = {{5772}},
  author       = {{Thery, Fabien Henri and Martina, Lia and Asselman, Caroline and Repo, Heidi and Zhang, Y and Sedeyn, Koen and Moschonas, Georgios and Bredow, C and Teo, QW and Zhang, J and Vessely, M and Leandro, Kevin and Eggermont, Denzel and De Sutter, Delphine and Boucher, Katie and Hochepied, Tino and Festjens, Nele and Callewaert, Nico and Saelens, Xavier and Dermaut, Bart and Knobeloch, KP and Beling, A and Sanyal, S and Radoshevich, L and Eyckerman, Sven and Impens, Francis}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{INTERFERON-STIMULATED GENE,PAPAIN-LIKE PROTEASE,LISTERIA-MONOCYTOGENES,MOYAMOYA-DISEASE,HUMAN INTERACTOME,MYCOBACTERIUM-TUBERCULOSIS,ISG15,LIGASE,VIRUS,AUTOPHAGY}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{21}},
  title        = {{Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-26061-w}},
  volume       = {{12}},
  year         = {{2021}},
}

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