PMID- 26045048
OWN - NLM
STAT- MEDLINE
DCOM- 20160909
LR  - 20211203
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 23
IP  - 1
DP  - 2016 Jan
TI  - Protein kinase D1/2 is involved in the maturation of multivesicular bodies and 
      secretion of exosomes in T and B lymphocytes.
PG  - 99-109
LID - 10.1038/cdd.2015.72 [doi]
AB  - Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal 
      vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. 
      In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal 
      exosomes' following activation-induced fusion of the MVB with the plasma 
      membrane. Diacylglycerol (DAG) and diacylglycerol kinase alpha (DGKalpha) regulate MVB 
      maturation and polarized traffic, as well as subsequent secretion of 
      pro-apoptotic exosomes, but the molecular basis underlying these phenomena 
      remains unclear. Here we identify protein kinase D (PKD) family members as DAG 
      effectors involved in MVB genesis and secretion. We show that the inducible 
      secretion of exosomes is enhanced when a constitutively active PKD1 mutant is 
      expressed in T lymphocytes, whereas exosome secretion is impaired in 
      PKD2-deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of 
      PKD2-deficient T lymphoblasts showed the presence of large, immature MVB-like 
      vesicles and demonstrated defects in cytotoxic activity and in activation-induced 
      cell death. Using pharmacological and genetic tools, we show that DGKalpha regulates 
      PKD1/2 subcellular localization and activation. Our studies demonstrate that 
      PKD1/2 is a key regulator of MVB maturation and exosome secretion, and 
      constitutes a mediator of the DGKalpha effect on MVB secretory traffic.
FAU - Mazzeo, C
AU  - Mazzeo C
AD  - Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols 
      CSIC-UAM Madrid, Madrid, Spain.
FAU - Calvo, V
AU  - Calvo V
AD  - Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols 
      CSIC-UAM Madrid, Madrid, Spain.
FAU - Alonso, R
AU  - Alonso R
AD  - Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols 
      CSIC-UAM Madrid, Madrid, Spain.
FAU - Merida, I
AU  - Merida I
AD  - Department of Immunology and Oncology, Centro Nacional de Biotecnologia CSIC, 
      Madrid, Spain.
FAU - Izquierdo, M
AU  - Izquierdo M
AUID- ORCID: 0000-0002-7701-1002
AD  - Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols 
      CSIC-UAM Madrid, Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150605
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Fasl protein, mouse)
RN  - 0 (Protein Kinase D2)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.107 (Diacylglycerol Kinase)
RN  - EC 2.7.10.- (protein kinase D)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/metabolism
MH  - Cell Death/*genetics
MH  - Diacylglycerol Kinase/*genetics/metabolism
MH  - Exosomes/genetics/metabolism
MH  - Fas Ligand Protein
MH  - Mice
MH  - Multivesicular Bodies/genetics/metabolism
MH  - Protein Kinase C/*genetics/metabolism
MH  - Protein Kinase D2
MH  - Protein Kinases/*genetics/metabolism
MH  - T-Lymphocytes/metabolism
PMC - PMC4815981
EDAT- 2015/06/06 06:00
MHDA- 2016/09/10 06:00
PMCR- 2017/01/01
CRDT- 2015/06/06 06:00
PHST- 2014/10/02 00:00 [received]
PHST- 2015/04/22 00:00 [revised]
PHST- 2015/04/28 00:00 [accepted]
PHST- 2015/06/06 06:00 [entrez]
PHST- 2015/06/06 06:00 [pubmed]
PHST- 2016/09/10 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - cdd201572 [pii]
AID - 10.1038/cdd.2015.72 [doi]
PST - ppublish
SO  - Cell Death Differ. 2016 Jan;23(1):99-109. doi: 10.1038/cdd.2015.72. Epub 2015 Jun 
      5.