Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Bacteriophage T7
/ metabolism
Chemokines
/ genetics
Glycation End Products, Advanced
/ metabolism
HEK293 Cells
Humans
Inflammation
/ metabolism
Macrophages
/ metabolism
Mice
Mice, Inbred C57BL
Models, Biological
Molecular Targeted Therapy
Peptides
/ metabolism
Phosphoproteins
/ metabolism
Protein Binding
Protein Domains
RAW 264.7 Cells
RNA, Messenger
/ genetics
Receptor for Advanced Glycation End Products
/ chemistry
Sepsis
/ drug therapy
Signal Transduction
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 01 2021
12 01 2021
Historique:
received:
25
04
2020
accepted:
07
12
2020
entrez:
13
1
2021
pubmed:
14
1
2021
medline:
22
1
2021
Statut:
epublish
Résumé
Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.
Identifiants
pubmed: 33436632
doi: 10.1038/s41467-020-20577-3
pii: 10.1038/s41467-020-20577-3
pmc: PMC7804203
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Chemokines
0
Glycation End Products, Advanced
0
Peptides
0
Phosphoproteins
0
RNA, Messenger
0
Receptor for Advanced Glycation End Products
0
SLP-76 signal Transducing adaptor proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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