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IMMUNOLOGY

DPP9 restrains NLRP1 activation

Nature Structural & Molecular Biology volume 28, pages 333–336 (2021)Cite this article

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NLRP1 was the first inflammasome-forming sensor to be identified, but only recently has its mode of action been in the spotlight. Two groups now report cryo-EM structures demonstrating how NLRP1 is kept in check by the dipeptidyl peptidase DPP9, and they illuminate how DPP9 inhibition leads to NLRP1 inflammasome activation.

Inflammasomes are cytoplasmic sensing machineries that have evolved to detect the presence of pathogenic non-self agents or the perturbation of cellular homeostasis. Unlike other non-self-recognition systems, inflammasomes can be considered as last-resort defense strategies in that their activation can ultimately result in cellular demise. Along with inducing cell death, inflammasome activation results in the maturation of highly proinflammatory cytokines that can initiate potent defense mechanisms. To avoid accidental engagement of these potentially dangerous responses, inflammasome activation needs to be tightly regulated. The minimal inflammasome signaling unit consists of a sensor protein and pro-caspase-1, which gets recruited to this sensor upon activation. Most inflammasomes, however, make use of the adapter protein ASC, which serves to amplify the response and to introduce a threshold-restricted signaling behavior. For most inflammasomes, the sensor protein itself is able to oligomerize, which occurs upon activation. This process serves to form a seed-like structure that initiates the assembly of the adapter protein ASC, which forms a filamentous signal hub. Upon recruitment, pro-caspase-1 is activated at this complex so that it can process its substrates. This includes certain cytokines of the interleukin-1 family, as well as the pore-forming molecule GSDMD, which triggers the lytic cell death of pyroptosis.

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Fig. 1: Keeping NLRP1 in check.
Fig. 2: Modes of NLRP1 activation.

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Acknowledgements

This work was supported by the Fondation Bettencourt Schueller and by the Deutsche Forschungsgemeinschaft CRC 1054/B17 (Project-ID 210592381) and CRC 1403/A03 (Project-ID 414786233).

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  1. Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany

    Stefan Bauernfried & Veit Hornung

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  1. Stefan Bauernfried
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Correspondence to Veit Hornung.

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Bauernfried, S., Hornung, V. DPP9 restrains NLRP1 activation. Nat Struct Mol Biol 28, 333–336 (2021). https://doi.org/10.1038/s41594-021-00580-y

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