Priming enables a NEK7-independent route of NLRP3 activation

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 primingrather than activationfactor that can work in synergy or redundancy with other priming pathways to accelerate inflammasome activation.

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

“…These studies suggest NEK7 is involved primarily in NLRP3 activation but a recent preprint study by Schmacke et al. argues that NEK7 functions as an NLRP3 priming factor 83 . Importantly, this study also identified a NEK7‐independent mechanism of NLRP3 activation, involving TAK1‐driven posttranslational priming of NLRP3.…”

“…The authors suggest that previous studies were conducted in murine models while their research utilized human induced pluripotent stem cell‐derived Mϕs as the explanation for these differing results. This study highlights the complexity of NLRP3 regulation via NEK7 and the need for further investigation, particularly as determining the precise role played by NEK7 could identify it as a therapeutic target in NLRP3 inflammasome‐mediated diseases 83–86 …”

Priming is dispensable for NLRP3 inflammasome activation in human monocytes

“…TAK1 kinase is described to regulate the canonical NLRP3 inflammasome at both priming and activation stages, by either mediating transcriptional priming through its role in NF-κB signalling downstream of TLR4 [46] or by controlling lysosomal rupture that leads to NLRP3 assembly and activation [38]. More recently, TAK1 has been suggested to mediate inflammasome activation via non transcriptional priming [40]. It was reported that the requirement for the NLRP3-binding protein NEK7 to form and active NLRP3 inflammasome [39] can be bypassed via TAK1 mediated potential post translational priming of NLRP3 [40].…”

“…More recently, TAK1 has been suggested to mediate inflammasome activation via non transcriptional priming [40]. It was reported that the requirement for the NLRP3-binding protein NEK7 to form and active NLRP3 inflammasome [39] can be bypassed via TAK1 mediated potential post translational priming of NLRP3 [40]. It is therefore not clear whether TAK1 plays a role in a setting where TLR4 is not engaged.…”

“…TAK1 (transforming growth factor beta-activated kinase 1) can mediate canonical NLRP3 inflammasome assembly and ASC oligomerisation independently of its role in the NF-kB pathway (inflammasome priming signal) [38]. It has been recently suggested that in human cells, the inflammasome priming step allows for NLRP3 posttranslational modifications that lead to cells bypassing the requirement for NEK7, thought to be a critical co-factor for canonical NLRP3 activation [39], in a TAK1 dependent manner [40]. Therefore, we investigated whether TAK1 activity is a requirement for NLRP3 activation in the absence of priming in human monocytes.…”