PMID- 29970602
OWN - NLM
STAT- MEDLINE
DCOM- 20191011
LR  - 20191011
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 11
IP  - 537
DP  - 2018 Jul 3
TI  - Tomosyn functions as a PKCdelta-regulated fusion clamp in mast cell degranulation.
LID - eaan4350 [pii]
LID - 10.1126/scisignal.aan4350 [doi]
AB  - Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) 
      family proteins mediate membrane fusion critical for vesicular transport and 
      cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for 
      degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the 
      Fcepsilon receptor (FcepsilonRI). We investigated the mechanisms downstream of receptor 
      activation that control degranulation. We found that the SNARE binding protein 
      tomosyn-1 (also known as STXBP5) inhibited FcepsilonRI-stimulated degranulation of mast 
      cells. After mast cell activation, tomosyn-1 was phosphorylated on serine and 
      threonine residues, dissociated from the SNARE protein syntaxin 4 (STX4), and 
      associated with STX3. We identified PKCdelta as the major kinase required for 
      tomosyn-1 threonine phosphorylation and for regulation of the interaction with 
      STXs. Incubation with high IgE concentrations increased tomosyn-1 abundance in 
      cultured mast cells. Similarly, in basophils from allergic patients with high 
      amounts of serum IgE, the abundance of tomosyn-1 was increased as compared to 
      that in patients with normal IgE concentrations. Our findings identified 
      tomosyn-1 as an inhibitor of mast cell degranulation that required PKCdelta to switch 
      its interaction with STX partners during fusion. We suggest that the IgE-mediated 
      increase in tomosyn-1 abundance in allergic patients may represent a 
      counterregulatory mechanism to limit disease development.
CI  - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Madera-Salcedo, Iris K
AU  - Madera-Salcedo IK
AUID- ORCID: 0000-0002-0741-9248
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Danelli, Luca
AU  - Danelli L
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Tiwari, Neeraj
AU  - Tiwari N
AUID- ORCID: 0000-0003-3911-4809
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Dema, Barbara
AU  - Dema B
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Pacreau, Emeline
AU  - Pacreau E
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Vibhushan, Shamila
AU  - Vibhushan S
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Birnbaum, Joelle
AU  - Birnbaum J
AD  - Aix-Marseille University, Assistance Publique Hopitaux de Marseille (APHM), 
      Service de Dermatologie, Hopital de la Timone, Marseille, France.
FAU - Agabriel, Chantal
AU  - Agabriel C
AD  - Aix-Marseille University, APHM, Service de Pediatrie Multidisciplinaire, Hopital 
      de la Timone, Marseille, France.
FAU - Liabeuf, Valerie
AU  - Liabeuf V
AD  - Aix-Marseille University, Assistance Publique Hopitaux de Marseille (APHM), 
      Service de Dermatologie, Hopital de la Timone, Marseille, France.
FAU - Klingebiel, Caroline
AU  - Klingebiel C
AUID- ORCID: 0000-0002-9069-6931
AD  - Laboratoire BIOPLUS, 22 rue Montgrand, 13006 Marseille, France.
FAU - Menasche, Gael
AU  - Menasche G
AUID- ORCID: 0000-0001-6671-3642
AD  - INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune 
      System, F-75015 Paris, France.
AD  - Paris Descartes University-Sorbonne Paris Cite, Imagine Institute, F-75015 Paris, 
      France.
FAU - Macias-Silva, Marina
AU  - Macias-Silva M
AUID- ORCID: 0000-0002-3972-0983
AD  - Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico 
      City, Mexico.
FAU - Benhamou, Marc
AU  - Benhamou M
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Charles, Nicolas
AU  - Charles N
AUID- ORCID: 0000-0002-5416-5834
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
FAU - Gonzalez-Espinosa, Claudia
AU  - Gonzalez-Espinosa C
AUID- ORCID: 0000-0001-7332-3829
AD  - Departamento de Farmacobiologia, Cinvestav, Sede Sur, Mexico City, Mexico.
FAU - Vitte, Joana
AU  - Vitte J
AUID- ORCID: 0000-0002-3344-9408
AD  - Aix-Marseille University, APHM, Laboratoire d'Immunologie, Institut Hopital 
      Universitaire (IHU) Mediterranee Infection, Marseille, France.
AD  - INSERM UMR 1067, Marseille, France.
AD  - Aix-Marseille University, CNRS UMR 7333, Marseille, France.
FAU - Blank, Ulrich
AU  - Blank U
AUID- ORCID: 0000-0002-2661-2983
AD  - INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France. 
      ulrich.blank@inserm.fr.
AD  - CNRS ERL8252, Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, Faculte de Medecine, Site Xavier 
      Bichat, Paris, France, Inflamex Laboratory of Excellence, Paris, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180703
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Qa-SNARE Proteins)
RN  - 0 (R-SNARE Proteins)
RN  - 0 (Receptors, IgE)
RN  - 0 (STXBP5 protein, human)
RN  - 0 (tomosyn protein, mouse)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
SB  - IM
MH  - Animals
MH  - *Cell Degranulation
MH  - Cells, Cultured
MH  - *Exocytosis
MH  - Humans
MH  - Immunoglobulin E/metabolism
MH  - Mast Cells/cytology/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Phosphorylation
MH  - Protein Kinase C-delta/genetics/*metabolism
MH  - Qa-SNARE Proteins/metabolism
MH  - R-SNARE Proteins/genetics/*metabolism
MH  - Rats
MH  - Receptors, IgE/metabolism
MH  - Retrospective Studies
EDAT- 2018/07/05 06:00
MHDA- 2019/10/12 06:00
CRDT- 2018/07/05 06:00
PHST- 2018/07/05 06:00 [entrez]
PHST- 2018/07/05 06:00 [pubmed]
PHST- 2019/10/12 06:00 [medline]
AID - 11/537/eaan4350 [pii]
AID - 10.1126/scisignal.aan4350 [doi]
PST - epublish
SO  - Sci Signal. 2018 Jul 3;11(537):eaan4350. doi: 10.1126/scisignal.aan4350.