Protein kinase D at the Golgi controls NLRP3 inflammasome activation

Zhang, Zhi Rong; Mészáros, Gyula; He, Wanting; Xu, Yanfang; Magliarelli, Helena de Fatima; Mailly, Laurent; Mihlan, Michael; Liu, Yansheng; Gámez, Marta Puig; Goginashvili, Alexander; Pasquier, Adrien; Bielska, Olga; Neven, Bénédicte; Quartier, Pierre; Aebersold, Rudolf; Baumert, Thomas F.; Georgel, Philippe; Han, Jiahuai; Ricci, Roméo

doi:10.1084/jem.20162040

Cited by 232 publications

(257 citation statements)

References 74 publications

(117 reference statements)

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“…In agreement with our results, a recent study demonstrated that NLRP3 inflammasome agonists induce mitochondrial clustering around the Golgi, at which protein kinase D phosphorylates NLRP3 to promote assembly of the NLRP3 inflammasome (38). Additionally, the authors showed that disruption of Golgi integrity by BFA treatment blocks NLRP3 inflammasome activation.…”

Section: Discussionsupporting

confidence: 93%

“…However, it remains elusive how NLRP3 is capable of sensing cytosolic alterations upon stimulation with diverse NLRP3activating agonists. Recent studies demonstrated that the intracellular organelle network might be important for the assembly of NLRP3 inflammasome, including the mitochondrial translocation into the perinuclear regions of macrophages upon NLRP3-activating stimulation (19,21,38). This mitochondria-specific spatial rearrangement might interact with ER to form mitochondriaassociated ER membranes, which could serve as a crucial platform for the formation of NLRP3 inflammasome.…”

Section: Discussionmentioning

confidence: 99%

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Brefeldin A–sensitive ER‐Golgi vesicle trafficking contributes to NLRP3‐dependent caspase‐1 activation

et al. 2018

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Endoplasmic reticulum (ER)‐Golgi vesicle trafficking plays a pivotal role in the conventional secretory pathway of many cytokines; however, the precise release mechanism of a major inflammasome mediator, IL‐1β, is not thought to follow the conventional ER‐Golgi route and remains elusive. Here, we found that perturbation of ER‐Golgi trafficking by brefeldin A (BFA) treatment attenuated nucleotide‐binding oligomerization domain‐like receptor family, pyrin–domain–containing 3 (NLRP3) inflammasome activation in mouse bone marrow–derived macrophages (BMDMs). BFA treatment inhibited NLRP3‐mediated inflammasome assembly and caspase‐1 activation but did not block IL‐1β secretion from BMDMs following BFA administration after NLRP3 inflammasome activation. Consistently, short‐hairpin RNA–dependent knockdown of BFA‐inhibited guanine nucleotide‐exchange protein 1 (BIG1), a molecular target of BFA and an initiator of Golgi‐specific vesicle trafficking, abolished NLRP3‐dependent apoptosis‐associated speck‐like protein containing a caspase‐recruitment domain oligomerization and caspase‐1 activation in BMDMs. Similarly, knockdown of Golgi‐specific BFA‐resistance guanine nucleotide exchange factor 1, another target of BFA, clearly attenuated NLRP3‐mediated caspase‐1 activation in BMDMs. Mechanistically, inhibition of BIGl‐mediated vesicle trafficking did not impair NLRP3‐activating signal 2‐promoted events, such as potassium efflux and mitochondrial rearrangement, but caused significant impairment of signal 1‐triggered priming steps, including NF‐κB–mediated pathways. These data suggest that BFA‐targeted vesicle trafficking at the Golgi contributes to activation of the NLRP3 inflammasome signaling.—Hong, S., Hwang, I., Gim, E., Yang, J., Park, S., Yoon, S.‐H., Lee, W.‐W., Yu, J.‐W. Brefeldin A–sensitive ER‐Golgi vesicle trafficking contributes to NLRP3‐dependent caspase‐1 activation. FASEB J. 33, 4547–4558 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Brefeldin A–sensitive ER‐Golgi vesicle trafficking contributes to NLRP3‐dependent caspase‐1 activation

et al. 2018

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“…Licensing of sensors for activation may include phosphorylation/dephosphorylation (NLRC4, NLRP3, Pyrin) and deubiquitination (NLRP3), while negative regulation is exemplified by the recruitment of the decoy Pyrin‐only protein Pop3 that binds to AIM2 and IFI16 to prevent the recruitment of ASC . Additionally, recent work has demonstrated that the sensor concentration can be regulated at the level of subcellular compartments . Expression levels of pro‐IL1β and pro‐IL18 seem to determine which cytokines are released upon inflammasome activation.…”

Section: Assembly and Regulation Of Asc Specksmentioning

confidence: 99%

“…35 Additionally, recent work has demonstrated that the sensor concentration can be regulated at the level of subcellular compartments. 36 Expression levels of pro-IL1β and pro-IL18 seem to determine which cytokines are released upon inflammasome activation.…”

Section: Assembly and Regulation Of Asc Specksmentioning

confidence: 99%

The intra‐ and extracellular functions of ASC specks

Franklin

Latz

Schmidt

2017

Immunological Reviews

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Inflammasomes are the central signaling hubs of the inflammatory response. They process cytosolic evidence of infection, cell damage, or metabolic disturbances, and elicit a pro-inflammatory response mediated by members of the interleukin-1 family of cytokines and pyroptotoic cell death. On the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC. Once a tunable threshold is reached, cooperative assembly of ASC into linear filaments and their condensation into macromolecular ASC specks promotes an all-or-none response. These structures are highly regulated and provide a unique signaling platform or compartment to control the activity of caspase-1 and likely other effectors. Emerging evidence indicates that ASC specks are also released from inflammasome-activated cells and accumulate in inflamed tissues, where they can continue to mature cytokines or be internalized by surrounding cells to further nucleate ASC specks in their cytosol. Little is known about the mechanisms governing ASC speck release, uptake, and endosomal escape, as well as its contribution to inflammation and disease. Here, we describe the different outcomes of inflammasome activation and discuss the potential function of extracellular ASC specks. We highlight gaps in our understanding of this central process of inflammation, which may have direct consequences on the modulation of host responses and chronic inflammation.

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“…En particulier NEK7 (NIMA-related protein kinase 7), qui se lie à NLRP3, est nécessaire à l'assemblage de l'inflammasome auquel elle participe, mais son activité kinase n'est pas essentielle [42]. Très récemment, il a été montré que la phosphorylation de la sérine S295 de NLRP3 par les PKD (protein kinase D) 1-3, activées en aval de la PLC et du DAG (diacylglycérol) serait nécessaire à l'assemblage de l'inflammasome [43]. Les mutants S295A et S295E, qui miment respectivement les états déphosphorylé et phosphorylé de cette sérine, sont tous deux inactifs.…”

Section: Modifications Post-traductionnelles De L'inflammasome Nlrp3 unclassified

NLRP3, un inflammasome sous contrôle

Groslambert

2018

Med Sci (Paris)

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> La réponse immunitaire innée protège l'organisme par la détection rapide des agents pathogènes et des lésions via des récepteurs spéciali-sés, dont NLRP3. Celui-ci assemble un inflammasome, un complexe cytosolique de signalisation qui active la caspase-1, contrôle la libération de cytokines et de facteurs inflammatoires produits dans le cytosol comme les interleukines 1 / . Les pathologies inflammatoires associées à NLRP3, dont la goutte, révèlent la nécessité d'un contrôle étroit de son activité. Cette revue présente les avancées sur la signalisation du priming (ou amorçage) du complexe puis de son activation avec une attention particulière sur le rôle des modifications post-traductionnelles de NLRP3. < cytokines et d'autres facteurs intracellulaires pro-inflammatoires dont l'IL-1 La mort par pyroptose de cellules infectées permet d'éliminer en parallèle les niches de réplication des pathogènes intracellulaires. La structure des inflammasomes dits non-canoniques, associés à la caspase-11, ou 4 et 5 chez l'homme, reste mal connue. Les inflammasomes canoniques, qui sont eux, associés à la caspase-1, sont assemblés par des récepteurs cytosoliques de la famille des NLR (nucleotide-binding domain leucin-rich repeat) ou ALR (Aim2-like receptors). Ces récepteurs s'oligomérisent pour former une plateforme de nucléation pour des filaments formés par la protéine adaptatrice ASC (apoptosis-associated speck-like protein containing a CARD domain, aussi appelé PYCARD, CARD5, TMS1, Q9ULZ3), dont la surface permet, à son tour, la nucléation de filaments de pro-caspase-1 [4]. Ces inflammasomes forment des specks (ou structures ponctiformes) d'une taille de l'ordre du micron, visibles en microscopie, et qui sont uniques pour une cellule. NLRP3 (nucleotide-binding domain leucin-rich repeat [LRR] and pyrin-containing receptor 3, nommé également cryopyrin, CIAS1 [cold autoinflammatory syndrome 1 protein] ou NALP3 [NACHT, LRR and PYD domains-containing protein 3]) a été initialement décrit pour son association génétique avec des syndromes auto-inflammatoires héréditaires monogéniques dominants, nommés CAPS (cryopyrin-associated periodic syndrome) ou cryopyrinopathies [5]. Depuis, NLRP3 a été impliqué dans de nombreuses pathologies multifactorielles à composante inflammatoire, dont l'arthrite goutteuse, l'athérosclérose, le diabète de type 2 et la stéatose hépatique non-alcoolique [6,7]. Il est également impliqué dans plusieurs maladies neurodégénéra-tives, dont la sclérose en plaques et les maladies d'Alzheimer et de Parkinson, ainsi que dans les pathologies associées au vieillissement [6][7][8][9]. NLRP3 est aussi important au cours des infections par diffé-rents pathogènes. Il intervient en effet dans la reconnaissance de

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Protein kinase D at the Golgi controls NLRP3 inflammasome activation

Cited by 232 publications

References 74 publications

Brefeldin A–sensitive ER‐Golgi vesicle trafficking contributes to NLRP3‐dependent caspase‐1 activation

Brefeldin A–sensitive ER‐Golgi vesicle trafficking contributes to NLRP3‐dependent caspase‐1 activation

The intra‐ and extracellular functions of ASC specks

NLRP3, un inflammasome sous contrôle

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