Priming enables a NEK7-independent route of NLRP3 activation

Schmacke, N. A.; Gaidt, M. M.; Szymanska, I.; O'Duill, F.; Stafford, C. A.; Chauhan, D.; Froehlich, A. L.; Nagl, D.; Pinci, F.; Schmid-Burgk, J. L.; Hornung, V.

doi:10.1101/799320

bioRxiv · 10.1101/799320

Priming enables a NEK7-independent route of NLRP3 activation

Schmacke, N. A.·Gaidt, M. M.·Szymanska, I.·O'Duill, F.·Stafford, C. A.·Chauhan, D.·Froehlich, A. L.·Nagl, D.·Pinci, F.·Schmid-Burgk, J. L.·Hornung, V.

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Abstract

The NLRP3 inflammasome plays a central role in antimicrobial defense, as well as in sterile inflammatory conditions. NLRP3 activity is governed by two independent signals. The first signal primes NLRP3, allowing it to respond to its activation signal. In the murine system, the mitotic spindle kinase NEK7 has been identified as a crucial factor in relaying the activation signal to NLRP3. Here we show that the requirement for NEK7 can be bypassed by TAK1-dependent post-translational priming. Under pro-inflammatory conditions that activate TAK1, NEK7 was dispensable for NLRP3 inflammasome formation in human and murine cells. Intriguingly, dissecting the NEK7 requirement in iPSC-derived primary human macrophages revealed that this NEK7-independent mechanism constitutes the predominant NLRP3 priming pathway in these cells. In summary, our results suggest that NEK7 functions as an NLRP3 priming - rather than activation - factor that can work in synergy or redundancy with other priming pathways to accelerate inflammasome activation.

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Schmacke, N. A., Gaidt, M. M., Szymanska, I., O'Duill, F., Stafford, C. A., Chauhan, D., Froehlich, A. L., Nagl, D., Pinci, F., Schmid-Burgk, J. L., Hornung, V.. 2019-10-09. Priming enables a NEK7-independent route of NLRP3 activation. https://doi.org/10.1101/799320

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