PMID- 28379543
OWN - NLM
STAT- MEDLINE
DCOM- 20170919
LR  - 20211204
IS  - 1362-4962 (Electronic)
IS  - 0305-1048 (Print)
IS  - 0305-1048 (Linking)
VI  - 45
IP  - 9
DP  - 2017 May 19
TI  - Intra-endosomal trafficking mediated by lysobisphosphatidic acid contributes to 
      intracellular release of phosphorothioate-modified antisense oligonucleotides.
PG  - 5309-5322
LID - 10.1093/nar/gkx231 [doi]
AB  - Antisense oligonucleotides (ASOs) with phosphorothioate (PS) linkages are broadly 
      used as research tools and therapeutic agents. Chemically modified PS-ASOs can 
      mediate efficient target reduction by site-specific cleavage of RNA through RNase 
      H1. PS-ASOs are known to be internalized via a number of endocytotic pathways and 
      are released from membrane-enclosed endocytotic organelles, mainly late endosomes 
      (LEs). This study was focused on the details of PS-ASO trafficking through 
      endocytic pathways. It was found that lysobisphosphatidic acid (LBPA) is required 
      for release of PS-ASOs from LEs. PS-ASOs exited early endosomes (EEs) rapidly 
      after internalization and became co-localized with LBPA by 2 hours in LEs. Inside 
      LEs, PS-ASOs and LBPA were co-localized in punctate, dot-like structures, likely 
      intraluminal vesicles (ILVs). Deactivation of LBPA using anti-LBPA antibody 
      significantly decreased PS-ASO activities without affecting total PS-ASO uptake. 
      Reduction of Alix also substantially decreased PS-ASO activities without 
      affecting total PS-ASO uptake. Furthermore, Alix reduction decreased LBPA levels 
      and limited co-localization of LBPA with PS-ASOs at ILVs inside LEs. Thus, the 
      fusion properties of ILVs, which are supported by LBPA, contribute to PS-ASO 
      intracellular release from LEs.
CI  - (c) The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic 
      Acids Research.
FAU - Wang, Shiyu
AU  - Wang S
AD  - Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle 
      Court, Carlsbad, CA 92010, USA.
FAU - Sun, Hong
AU  - Sun H
AD  - Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle 
      Court, Carlsbad, CA 92010, USA.
FAU - Tanowitz, Michael
AU  - Tanowitz M
AD  - Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc. 2855 Gazelle 
      Court, Carlsbad, CA 92010, USA.
FAU - Liang, Xue-Hai
AU  - Liang XH
AD  - Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle 
      Court, Carlsbad, CA 92010, USA.
FAU - Crooke, Stanley T
AU  - Crooke ST
AD  - Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle 
      Court, Carlsbad, CA 92010, USA.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Nucleic Acids Res
JT  - Nucleic acids research
JID - 0411011
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Endosomal Sorting Complexes Required for Transport)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Lysophospholipids)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Monoglycerides)
RN  - 0 (NPC1 protein, human)
RN  - 0 (Niemann-Pick C1 Protein)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (PDCD6IP protein, human)
RN  - 0 (Phosphorothioate Oligonucleotides)
RN  - 0 (bis(monoacylglyceryl)phosphate)
SB  - IM
MH  - Biological Transport
MH  - Calcium-Binding Proteins/metabolism
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line, Tumor
MH  - Endocytosis
MH  - Endosomal Sorting Complexes Required for Transport/metabolism
MH  - Endosomes/*metabolism
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Intracellular Space/*metabolism
MH  - Kinetics
MH  - Lysophospholipids/*metabolism
MH  - Membrane Glycoproteins/metabolism
MH  - Models, Biological
MH  - Monoglycerides/*metabolism
MH  - Niemann-Pick C1 Protein
MH  - Oligonucleotides, Antisense/chemistry/*metabolism
MH  - Phosphorothioate Oligonucleotides/*metabolism
PMC - PMC5605259
EDAT- 2017/04/06 06:00
MHDA- 2017/09/20 06:00
PMCR- 2017/04/03
CRDT- 2017/04/06 06:00
PHST- 2017/01/31 00:00 [received]
PHST- 2017/03/27 00:00 [accepted]
PHST- 2017/04/06 06:00 [pubmed]
PHST- 2017/09/20 06:00 [medline]
PHST- 2017/04/06 06:00 [entrez]
PHST- 2017/04/03 00:00 [pmc-release]
AID - 3100227 [pii]
AID - gkx231 [pii]
AID - 10.1093/nar/gkx231 [doi]
PST - ppublish
SO  - Nucleic Acids Res. 2017 May 19;45(9):5309-5322. doi: 10.1093/nar/gkx231.