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J Exp Med. 2017 Sep 4;214(9):2671-2693. doi: 10.1084/jem.20162040. Epub 2017 Jul 17.

Protein kinase D at the Golgi controls NLRP3 inflammasome activation.

Zhang Z1,2,3,4, Meszaros G1,2,3,4,5, He WT6, Xu Y1,2,3,4,7,8, de Fatima Magliarelli H1,2,3,4, Mailly L4,9, Mihlan M1,2,3,4, Liu Y10, Puig Gámez M1,2,3,4, Goginashvili A1,2,3,4, Pasquier A1,2,3,4, Bielska O1,2,3,4, Neven B11,12, Quartier P11,12, Aebersold R10,13, Baumert TF4,9,14, Georgel P4,15, Han J6, Ricci R16,2,3,4,5.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
2
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
3
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
4
Université de Strasbourg, Strasbourg, France.
5
Laboratoire de Biochimie et de Biologie Moléculaire, Nouvel Hôpital Civil, Strasbourg, France.
6
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
7
Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
8
State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Beijing, China.
9
Institut National de la Santé et de la Recherche Medicale (INSERM), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.
10
Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule, Zurich, Switzerland.
11
Institut IMAGINE, Sorbonne Paris Cité, Université Paris-Descartes, Paris, France.
12
Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France.
13
Faculty of Science, University of Zurich, Zurich, Switzerland.
14
Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
15
ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
16
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France romeo.ricci@igbmc.fr.

Abstract

The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes. Diacylglycerol (DAG) at the Golgi rapidly increases, recruiting protein kinase D (PKD), a key effector of DAG. Upon PKD inactivation, self-oligomerized NLRP3 is retained at MAMs adjacent to Golgi, blocking assembly of the active inflammasome. Importantly, phosphorylation of NLRP3 by PKD at the Golgi is sufficient to release NLRP3 from MAMs, resulting in assembly of the active inflammasome. Moreover, PKD inhibition prevents inflammasome autoactivation in peripheral blood mononuclear cells from patients carrying NLRP3 mutations. Hence, Golgi-mediated PKD signaling is required and sufficient for NLRP3 inflammasome activation.

PMID:
28716882
PMCID:
PMC5584123
DOI:
10.1084/jem.20162040
[Indexed for MEDLINE]
Free PMC Article

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