Download TLR4 signaling: negative regulation by degradation

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Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532-1542.
2. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650-665.
3. Levkowitz G, Waterman H, Ettenberg S, et al. Ubiq-
uitin ligase activity and tyrosine phosphorylation underlie
suppression of growth factor signaling by c-Cbl/Sli-1. Molecular Cell. 1999;4:1029-1040.
4. Yoon CH, Lee J, Jongeward GD, et al. Similarity of
sli-1, a regulator of vulval development in C. elegans, to the
mammalian proto-oncogene c-cbl. Science.
1995;269:1102-1105.
5. Zheng N, Wang P, Jeffrey PD, et al. Structure of a cCbl-UbcH7 complex: RING domain function in ubiquitinprotein ligases. Cell. 2000;102:533-539.
● ● ● IMMUNOBIOLOGY
Comment on Wang et al, page 962
TLR4 signaling: negative regulation
by
degradation
---------------------------------------------------------------------------------------------------------------Osamu Takeuchi and Shizuo Akira
OSAKA UNIVERSITY
In this issue of Blood, Wang and colleagues describe that small GTPase Rab7b
negatively regulates TLR4-mediated responses by promoting the translocation of
TLR4 into lysosomes for its degradation.
oll-like receptors (TLRs) play a critical
role in the recognition of microbial components in innate immune cells.1 Among 13
identified mammalian TLRs, TLR4 recognizes lipopolysaccharide (LPS) from Gramnegative bacteria. Activation of signaling cascades triggered by TLR4 stimulation leads to
the up-regulation of proinflammatory cytokine and chemokine genes. Although TLR4
signaling is critical for eradicating Gram-negative bacterial infection, excess production of
cytokines can cause endotoxic shock and
death.
Extensive studies have revealed that various host proteins act as negative regulators of
TLR4 signaling and prevent aberrant activation of TLR4 signaling.2 These proteins include SIGIRR, ST2, the splice variant of
MyD88 (MyD88s), IL-1R-associated kinase-M (IRAK-M), a protein associated with
TLR4 (PRAT4A), A20, Triad3A, and so on.
The complex mechanism of negative regulation of TLRs emphasizes that it is important
for prevention of uncontrolled immune activation in the host.
In this issue of Blood, Wang and colleagues
report a novel mechanism for negative regulation of TLR4 signaling. This mechanism involves Rab7b small GTPase, which localized
to lysosome-associated subcellular compartments. Rab7 has been shown to be involved in
membrane trafficking and lysosomal degradation of several receptors, such as antigotensin
T
794
II receptor EGFR and TrkA. The authors
show that siRNA-mediated knockdown of the
Rab7b gene in macrophages resulted in upregulation of LPS-induced proinflammatory
cytokine production. Reciprocally, overexpression of Rab7b suppressed TLR4-mediated production of cytokines as well as activa-
tion of intracellular signaling molecules. Upon
stimulation, TLR4 is internalized and recruited to the late endosomes/lysosomes
where Rab7b is located. In Rab7b-silenced
cells, the expression of TLR4 was higher than
in control cells, and translocation of TLR4
from early endosomes to late endosomes/lysosomes was delayed.
This study clearly demonstrates that the
down-regulation of TLR4 protein expression
by Rab7b plays a critical role in the control of
LPS responses. However, the mechanisms by
which Rab7b controls TLR4 trafficking in a
stimulant-dependent manner remain to be
clarified. Further, it is possible that lysosomemediated degradation is a common mechanism for the regulation of responses against
various TLR ligands. Future studies regarding spatiotemporal regulation of TLR signaling molecules in the cell will shed light on the
importance of membrane trafficking in the
control of innate immune responses.
Conflict-of-interest disclosure: The authors
declare no competing financial interests. ■
REFERENCES
1. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783-801.
2. Liew FY, Xu D, Brint EK, O’Neill LA. Negative
regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5:446-458.
● ● ● PHAGOCYTES
Comment on Haselmayer et al, page 1029
Platelets and leukocytes: aggregate
knowledge
---------------------------------------------------------------------------------------------------------------Alan D. Michelson and Peter E. Newburger
UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL
In this issue of Blood, Haselmayer and colleagues demonstrate that platelets express
the ligand for the triggering receptor expressed on myeloid cells 1 (TREM-1), and
show that its interaction with neutrophil TREM-1 amplifies neutrophil activation.
latelets adhere to neutrophils and monocytes via a number of receptor/counterreceptor pairs (see figure).1 Activated platelets
degranulate, thereby expressing platelet
surface P-selectin. The initial adhesion of
platelets to neutrophils and monocytes occurs via platelet surface P-selectin binding
to its constitutively expressed leukocyte
counterreceptor, P-selectin glycoprotein
ligand 1 (PSGL-1). Stabilization of leukocyte-platelet aggregates occurs via the bind-
P
ing of leukocyte surface Mac-1 (also known
as integrin ␣M␤2 and CD11b/CD18) to
platelet surface glycoprotein Ib (GPIb). In
addition, leukocyte surface Mac-1 binds to the
platelet surface integrin ␣IIb␤3 (with fibrinogen as a bridging molecule) and/or to platelet
surface junctional adhesion molecule 3 (JAM-3).
Haselmayer and colleagues have now identified an additional receptor/counterreceptor
pair involved in this process: neutrophil surface TREM-1 and platelet surface TREM-1
1 AUGUST 2007 I VOLUME 110, NUMBER 3
blood
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2007 110: 794
doi:10.1182/blood-2007-04-084475
TLR4 signaling: negative regulation by degradation
Osamu Takeuchi and Shizuo Akira
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