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NOD1 is super-activated through spatially-selective ubiquitination by the Salmonella effector SspH2

Cole Delyea, View ORCID ProfileShu Y. Luo, Bradley E. Dubrule, View ORCID ProfileOlivier Julien, View ORCID ProfileAmit P. Bhavsar
doi: https://doi.org/10.1101/2021.10.08.463692
Cole Delyea
1Department of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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Shu Y. Luo
2Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2R3 Canada
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Bradley E. Dubrule
1Department of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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Olivier Julien
2Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2R3 Canada
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  • ORCID record for Olivier Julien
Amit P. Bhavsar
1Department of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1 Canada
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  • For correspondence: amit.bhavsar@ualberta.ca
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ABSTRACT

As part of its pathogenesis, Salmonella enterica serovar Typhimurium delivers effector proteins into host cells. One effector is SspH2, a member of the novel E3 ubiquitin ligase family, interacts with, and enhances, NOD1 pro-inflammatory signaling, though the underlying mechanisms are unclear. Here, we report the novel discovery that SspH2 interacts with multiple members of the NLRC family to enhance pro-inflammatory signaling that results from targeted ubiquitination. We show that SspH2 modulates host innate immunity by interacting with both NOD1 and NOD2 in mammalian epithelial cell culture. We also show that SspH2 specifically interacts with the NBD and LRR domains of NOD1 and super-activates NOD1- and NOD2-mediated cytokine secretion via the NF-κB pathway. Mass spectrometry analyses identified lysine residues in NOD1 that were ubiquitinated after interaction with SspH2. Through NOD1 mutational analyses, we identified four key lysine residues that are required for NOD1 super-activation by SspH2, but not its basal activity. These critical lysine residues are positioned in the same region of NOD1 and define a surface on NOD1 that is targeted by SspH2. Overall, this work provides evidence for post-translational modification of NOD1 by ubiquitin, and uncovers a unique mechanism of spatially-selective ubiquitination to enhance the activation of an archetypal NLR.

SYNOPSIS SspH2 is an E3 ubiquitin ligase injected by Salmonella Typhimurium into host cells that induces pro-inflammatory signaling. The immune receptor, NOD1, is ubiquitinated in the presence of SspH2, resulting in increased pro-inflammatory cytokine secretion.

  • SspH2 super-activates NOD1 and NOD2 to increase pro-inflammatory cytokine secretion, in part, through the NF-κB pathway

  • Ubiquitin modification of NOD1 were identified by mass spectrometry

  • A specific region of NOD1 is targeted by SspH2 to enhance NOD1 activity.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Author information updated. Figures 1, 2, 4 and 6 revised.

  • https://massive.ucsd.edu/ProteoSAFe/static/massive.jsp

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 12, 2021.
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NOD1 is super-activated through spatially-selective ubiquitination by the Salmonella effector SspH2
Cole Delyea, Shu Y. Luo, Bradley E. Dubrule, Olivier Julien, Amit P. Bhavsar
bioRxiv 2021.10.08.463692; doi: https://doi.org/10.1101/2021.10.08.463692
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NOD1 is super-activated through spatially-selective ubiquitination by the Salmonella effector SspH2
Cole Delyea, Shu Y. Luo, Bradley E. Dubrule, Olivier Julien, Amit P. Bhavsar
bioRxiv 2021.10.08.463692; doi: https://doi.org/10.1101/2021.10.08.463692

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