HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation

Abstract

Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1β (IL-1β) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain–containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1β conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.

Physiological and Pathological Roles of Mammalian NEK7

“…Thereby, this phosphorylation modification of NEK7 suppressed its binding with NLRP3 and inhibited NLRP3 inflammasome activation (Yang et al, 2019). In addition, HDAC6-mediated MTOC localization of NLRP3 may ensure the engagement of centrosomal kinase NEK7 (Magupalli et al, 2020). These studies suggest the important role of NEK7 in NLRP3 inflammasome activation.…”

Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome

“…Inflammasomes consist of a sensor protein, such as NLRP3, which recognizes the insults and activates effector proteins: Caspase-1. The active Caspase-1 cleaves the inflammatory pro-IL-1β and pro-IL-18 to generate their mature forms, as well as gasdermin D, whose N-terminus domains auto-assemble into pores on the plasma membrane for the release of bioactive cytokines, thus inducing an inflammatory form of cell death known as pyroptosis ( Shi et al, 2015 ; Magupalli et al, 2020 ). Two temporally distinct events are required for the full activation of NLRP3-mediated inflammasome.…”

Targeting the NLRP3 Inflammasome via BTK

“…The positively charged PBM was shown to direct NLRP3 toward phospho-inositol-4-phosphate (PIP4)-rich membranes (e.g., Golgi and possibly endosomes or mitochondria-associated membranes) via charge interactions (Zhang et al, 2017;Chen and Chen, 2018;Seoane et al, 2020). On these membranes, NLRP3 is thought to oligomerize (Chen and Chen, 2018) but then dissociate and re-locate to the microtubule-organizing center (MTOC) where ASC and NEK7 are engaged (Magupalli et al, 2020). On a peptide level, phosphomodification of tyrosine residues in the PBM altered the charge of this region (Bittner et al, 2020, PrePrint) and therefore may support the translocation or release of NLRP3 from PI4P-rich membranes, which would enable HDAC-6/dynein-dependent transport toward the MTOC where NLPR3 was shown to assemble a macromolecular ASC-and caspase-1 containing inflammasome (Magupalli et al, 2020).…”

“…On these membranes, NLRP3 is thought to oligomerize (Chen and Chen, 2018) but then dissociate and re-locate to the microtubule-organizing center (MTOC) where ASC and NEK7 are engaged (Magupalli et al, 2020). On a peptide level, phosphomodification of tyrosine residues in the PBM altered the charge of this region (Bittner et al, 2020, PrePrint) and therefore may support the translocation or release of NLRP3 from PI4P-rich membranes, which would enable HDAC-6/dynein-dependent transport toward the MTOC where NLPR3 was shown to assemble a macromolecular ASC-and caspase-1 containing inflammasome (Magupalli et al, 2020). This would be similar to the described function of Protein Kinase D to promote membrane dissociation (Zhang et al, 2017), albeit the latter mechanism appears PBM-independent as the modified site, S295, locates outside the PBM, but may also involve charge repulsion upon serine phosphorylation.…”