Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:Q3V6T2 (
ape
)
2,133
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multimodular scaffold,
GIV
(a.k.a.
Girdin
), titrates such inflammatory response in macrophages. Upon challenge with either live microbes or microbe-derived lipopolysaccharides (a ligand for TLR4), macrophages with
GIV
mount a more tolerant (hypo-reactive) transcriptional response and suppress proinflammatory cytokines and signaling pathways (i.e., NFkB and
CREB
) downstream of TLR4 compared to their
GIV
-depleted counterparts. Myeloid-specific gene-depletion studies confirmed that the presence of
GIV
ameliorates dextran sodium sulfate-induced colitis and sepsis-induced death. The antiinflammatory actions of
GIV
are mediated via its C-terminally located TIR-like BB-loop (TILL) motif which binds the cytoplasmic TIR modules of TLR4 in a manner that precludes receptor dimerization; such dimerization is a prerequisite for proinflammatory signaling. Binding of
GIV
's TILL motif to TIR modules inhibits proinflammatory signaling via other TLRs, suggesting a convergent paradigm for fine-tuning macrophage inflammatory responses.
...
PMID:TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin. 3305 14
