PMID- 25505180
OWN - NLM
STAT- MEDLINE
DCOM- 20150505
LR  - 20220112
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 6
DP  - 2015 Feb 6
TI  - The neutral sphingomyelinase pathway regulates packaging of the prion protein 
      into exosomes.
PG  - 3455-67
LID - 10.1074/jbc.M114.605253 [doi]
AB  - Prion diseases are a group of transmissible, fatal neurodegenerative disorders 
      associated with the misfolding of the host-encoded prion protein, PrP(C), into a 
      disease-associated form, PrP(Sc). The transmissible prion agent is principally 
      formed of PrP(Sc) itself and is associated with extracellular vesicles known as 
      exosomes. Exosomes are released from cells both in vitro and in vivo, and have 
      been proposed as a mechanism by which prions spread intercellularly. The 
      biogenesis of exosomes occurs within the endosomal system, through formation of 
      intraluminal vesicles (ILVs), which are subsequently released from cells as 
      exosomes. ILV formation is known to be regulated by the endosomal sorting 
      complexes required for transport (ESCRT) machinery, although an alternative 
      neutral sphingomyelinase (nSMase) pathway has been suggested to also regulate 
      this process. Here, we investigate a role for the nSMase pathway in exosome 
      biogenesis and packaging of PrP into these vesicles. Inhibition of the nSMase 
      pathway using GW4869 revealed a role for the nSMase pathway in both exosome 
      formation and PrP packaging. In agreement, targeted knockdown of nSMase1 and 
      nSMase2 in mouse neurons using lentivirus-mediated RNAi also decreases exosome 
      release, demonstrating the nSMase pathway regulates the biogenesis and release of 
      exosomes. We also demonstrate that PrP(C) packaging is dependent on nSMase2, 
      whereas the packaging of disease-associated PrP(Sc) into exosomes occurs 
      independently of nSMase2. These findings provide further insight into prion 
      transmission and identify a pathway which directly assists exosome-mediated 
      transmission of prions.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Guo, Belinda B
AU  - Guo BB
AD  - From the Department of Biochemistry and Molecular Biology, The University of 
      Melbourne, VIC 3010, Australia and the Bio21 Molecular Science and Biotechnology 
      Institute, The University of Melbourne, VIC 3010, Australia.
FAU - Bellingham, Shayne A
AU  - Bellingham SA
AD  - From the Department of Biochemistry and Molecular Biology, The University of 
      Melbourne, VIC 3010, Australia and the Bio21 Molecular Science and Biotechnology 
      Institute, The University of Melbourne, VIC 3010, Australia 
      shayneb@unimelb.edu.au.
FAU - Hill, Andrew F
AU  - Hill AF
AD  - From the Department of Biochemistry and Molecular Biology, The University of 
      Melbourne, VIC 3010, Australia and the Bio21 Molecular Science and Biotechnology 
      Institute, The University of Melbourne, VIC 3010, Australia 
      a.hill@unimelb.edu.au.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141210
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Prions)
RN  - EC 3.1.4.12 (Smpd3 protein, mouse)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Exosomes/*metabolism
MH  - Humans
MH  - Mice
MH  - Neurons/metabolism
MH  - Prions/*metabolism
MH  - Sphingomyelin Phosphodiesterase/genetics/*metabolism
PMC - PMC4319014
OTO - NOTNLM
OT  - Ceramide
OT  - Exosome
OT  - Exosomes
OT  - Extracellular Vesicles
OT  - Neutral Sphingomyelinase
OT  - Prion
OT  - Prion Disease
OT  - nSMase2
EDAT- 2014/12/17 06:00
MHDA- 2015/05/06 06:00
PMCR- 2016/02/06
CRDT- 2014/12/16 06:00
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/05/06 06:00 [medline]
PHST- 2016/02/06 00:00 [pmc-release]
AID - S0021-9258(20)49193-8 [pii]
AID - M114.605253 [pii]
AID - 10.1074/jbc.M114.605253 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Feb 6;290(6):3455-67. doi: 10.1074/jbc.M114.605253. Epub 2014 
      Dec 10.