PMID- 23241879
OWN - NLM
STAT- MEDLINE
DCOM- 20130314
LR  - 20211021
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 190
IP  - 2
DP  - 2013 Jan 15
TI  - Cell-specific TLR9 trafficking in primary APCs of transgenic TLR9-GFP mice.
PG  - 695-702
LID - 10.4049/jimmunol.1202342 [doi]
AB  - Recognition of nucleic acids by TLR9 requires its trafficking from the 
      endoplasmic reticulum to endolysosomal compartments and its subsequent 
      proteolytic processing. Both processes depend on interactions of TLR9 with the 
      polytopic endoplasmic reticulum-resident protein UNC93B1. To examine the 
      intracellular behavior of TLR9 in primary APCs, we generated transgenic mice 
      expressing a TLR9-GFP fusion. The TLR9-GFP transgene is functional and is 
      proteolytically processed in resting bone marrow-derived macrophages (BMDMs), 
      dendritic cells, and B cells. Inhibition of cleavage impairs TLR9-dependent 
      responses in all primary APCs analyzed. The kinetics of TLR9-GFP processing in 
      BMDMs and B cells differs: in B cells, proteolysis occurs at a faster rate, 
      consistent with an almost exclusive localization to endolysosomes at the resting 
      state. In contrast to the joint requirement for cathepsins L and S for TLR9 
      cleavage in macrophages, TLR9-GFP cleavage depends on cathepsin L activity in B 
      cells. As expected, in BMDMs and B cells from UNC93B1 (3d) mutant mice, cleavage 
      of TLR9-GFP is essentially blocked, and the expression level of UNC93B1 appears 
      tightly correlated with TLR9-GFP cleavage. We conclude that proteolysis is a 
      universal requirement for TLR9 activation in the primary cell types tested, 
      however the cathepsin requirement, rate of cleavage, and intracellular behavior 
      of TLR9 varies. The observed differences in trafficking indicate the possibility 
      of distinct modes of endosomal content sampling to facilitate initiation of 
      TLR-driven responses in APCs.
FAU - Avalos, Ana M
AU  - Avalos AM
AD  - Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
FAU - Kirak, Oktay
AU  - Kirak O
FAU - Oelkers, J Margit
AU  - Oelkers JM
FAU - Pils, Marina C
AU  - Pils MC
FAU - Kim, You-Me
AU  - Kim YM
FAU - Ottinger, Matthias
AU  - Ottinger M
FAU - Jaenisch, Rudolf
AU  - Jaenisch R
FAU - Ploegh, Hidde L
AU  - Ploegh HL
FAU - Brinkmann, Melanie M
AU  - Brinkmann MM
LA  - eng
GR  - R01 GM100518/GM/NIGMS NIH HHS/United States
GR  - R37 HD045022/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121212
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Toll-Like Receptor 9)
RN  - 0 (UNC93B1 protein, mouse)
RN  - 147336-22-9 (Green Fluorescent Proteins)
SB  - IM
MH  - Animals
MH  - Antigen-Presenting Cells/*metabolism
MH  - B-Lymphocytes/metabolism
MH  - Bone Marrow Cells/metabolism
MH  - Cell Line
MH  - Endoplasmic Reticulum/metabolism
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - Humans
MH  - Lysosomes/metabolism
MH  - Macrophages/metabolism
MH  - Membrane Transport Proteins/genetics/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Stability
MH  - Protein Transport
MH  - Proteolysis
MH  - Signal Transduction
MH  - Toll-Like Receptor 9/*genetics/*metabolism
MH  - Transgenes
PMC - PMC3539690
EDAT- 2012/12/18 06:00
MHDA- 2013/03/15 06:00
PMCR- 2012/12/12
CRDT- 2012/12/18 06:00
PHST- 2012/12/18 06:00 [entrez]
PHST- 2012/12/18 06:00 [pubmed]
PHST- 2013/03/15 06:00 [medline]
PHST- 2012/12/12 00:00 [pmc-release]
AID - jimmunol.1202342 [pii]
AID - ji_1202342 [pii]
AID - 10.4049/jimmunol.1202342 [doi]
PST - ppublish
SO  - J Immunol. 2013 Jan 15;190(2):695-702. doi: 10.4049/jimmunol.1202342. Epub 2012 
      Dec 12.