NOD1 mediates non-canonical inflammasome processing of interleukin-18 in epithelial cells to Helicobacter pylori infection.

Tran, L. S.; Ying, L.; D'Costa, K.; Wray-McCann, G.; Kerr, G.; Le, L.; Allison, C. C.; Ferrand, J.; Chaudhry, H.; Emery, J.; De Paoli, A.; Creed, S.; Kaparakis-Liaskos, M.; Como, J.; Dowling, J.; Johanesen, P. A.; Kufer, T. A.; Pedersen, J. S.; Mansell, A.; Philpott, D. J.; Elgass, K.; Abud, H. E.; Nachbur, U.; Croker, B. A.; Masters, S. L.; Ferrero, R. L.

doi:10.1101/587212

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bioRxiv · 10.1101/587212

NOD1 mediates non-canonical inflammasome processing of interleukin-18 in epithelial cells to Helicobacter pylori infection.

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Abstract

The interleukin-1 family members, IL-1{beta} and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1{beta} processing in myeloid cells have been extensively studied, those involved in IL-18 processing, particularly in non-myeloid cells, are still poorly understood. Here, we have identified the cytosolic sensor NOD1 as a key regulator of IL-18 processing in epithelial cells responding to Helicobacter pylori infection. Importantly, NOD1 processing of IL-18 occurs independently of the canonical inflammasome proteins, NLRP3 and ASC. Instead, NOD1 interacts directly with caspase-1 via homotypic binding of caspase-activation recruitment domains. We show that IL-18 is important in maintaining tissue homeostasis and protecting against pre-neoplastic changes due to gastric H. pylori infection. These findings reveal an unanticipated role for NOD1 in a new type of inflammasome that regulates epithelial cell production of bioactive IL-18 with tissue protective functions.

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Tran, L. S., Ying, L., D'Costa, K., Wray-McCann, G., Kerr, G., Le, L., Allison, C. C., Ferrand, J., Chaudhry, H., Emery, J., De Paoli, A., Creed, S., Kaparakis-Liaskos, M., Como, J., Dowling, J., Johanesen, P. A., Kufer, T. A., Pedersen, J. S., Mansell, A., Philpott, D. J., Elgass, K., Abud, H. E., Nachbur, U., Croker, B. A., Masters, S. L., Ferrero, R. L.. 2019-03-24. NOD1 mediates non-canonical inflammasome processing of interleukin-18 in epithelial cells to Helicobacter pylori infection.. https://doi.org/10.1101/587212

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