Editors' ChoiceImmunology

PKD and inflammation

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Science Signaling  19 Sep 2017:
Vol. 10, Issue 497, eaap9727
DOI: 10.1126/scisignal.aap9727

Protein kinase D signaling at the Golgi is required for activation of the NLRP3 inflammasome.

Inflammasomes are cytosolic multiprotein complexes that assemble in response to pathogen- or damage-associated signals and lead to the processing and secretion of inflammatory cytokines, such as interleukin-1β (IL-1β). The NLRP3 inflammasome is activated by various stimuli in a two-step process. First, pattern recognition receptor or cytokine receptor signaling stimulates expression of the genes encoding NLRP3 and pro-IL-1β. Second, a danger signal induces the assembly of NLRP3 with the adaptor protein ASC and caspase-1, which processes pro-IL-1β. Inflammasome assembly is associated with the phospholipase C (PLC)–dependent release of Ca2+ from the endoplasmic reticulum (ER) and its uptake by mitochondria, which causes damage and the release of factors that stimulate inflammasome assembly. Zhang et al. found that another PLC-dependent product, diacylglycerol (DAG), and its effector protein kinase D (PKD) were required for NLRP3 inflammasome activation. Treatment of macrophages with inflammasome activators resulted in the accumulation of DAG at the Golgi near mitochondria-associated ER membranes (MAMs) that were enriched in NLRP3. This in turn led to the recruitment and activation of PKD at the Golgi. Inhibition or knockdown of PKD isoforms prevented the recruitment of ASC to NLRP3 and blocked NLRP3 activation. Compared with vehicle-pretreated mice, mice pretreated with a PKD inhibitor before exposure to the TLR4 agonist LPS had reduced amounts of serum IL-1β. Inactivation of PKD prevented NLRP3 from being released from MAMs to the cytosol, an event that depended on the phosphorylation of NLRP3 at Ser293 by PKD. Patients with cryopyrin-associated periodic syndrome (CAPS) have mutations in NLRP3 that result in uncontrolled NLRP3 oligomerization and activation, resulting in inflammation. Treatment of PBMCs from CAPS patients with a PKD inhibitor reduced IL-1β secretion, suggesting that PKD can act downstream of NLRP3 oligomerization. Together, these data suggest that PKD signaling at the Golgi is required for NLRP3 inflammasome activation.

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