TY  - JOUR
AU  - Hering, Marvin
AU  - Madi, Alaa Abdelghani Mohamed
AU  - Sandhoff, Roger
AU  - Ma, Sicong
AU  - Wu, Jingxia
AU  - Mieg, Alessa
AU  - Richter, Karsten
AU  - Mohr, Kerstin
AU  - Knabe, Nora
AU  - Stichling, Diana
AU  - Poschet, Gernot
AU  - Bestvater, Felix
AU  - Frank, Larissa Johanna
AU  - Utikal, Jochen
AU  - Umansky, Viktor
AU  - Cui, Guoliang
TI  - Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-01498
SP  - 6067
PY  - 2024
N1  - #EA:D192#EA:A370#LA:D192# / HI-TRON
AB  - After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.
KW  - Animals
KW  - Toll-Like Receptor 4: metabolism
KW  - Sepsis: metabolism
KW  - Macrophages: metabolism
KW  - Myeloid Differentiation Factor 88: metabolism
KW  - Mice
KW  - Sphingosine: analogs & derivatives
KW  - Sphingosine: metabolism
KW  - Melanoma: metabolism
KW  - Melanoma: pathology
KW  - Melanoma: genetics
KW  - Serine C-Palmitoyltransferase: metabolism
KW  - Serine C-Palmitoyltransferase: genetics
KW  - Humans
KW  - Signal Transduction
KW  - Disease Models, Animal
KW  - Inflammation: metabolism
KW  - Receptors, Interleukin-1: metabolism
KW  - Receptors, Interleukin-1: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Membrane Glycoproteins: genetics
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - HEK293 Cells
KW  - Lipopolysaccharides
KW  - Toll-Like Receptor 4 (NLM Chemicals)
KW  - Myeloid Differentiation Factor 88 (NLM Chemicals)
KW  - Sphingosine (NLM Chemicals)
KW  - Tlr4 protein, mouse (NLM Chemicals)
KW  - Serine C-Palmitoyltransferase (NLM Chemicals)
KW  - safingol (NLM Chemicals)
KW  - Receptors, Interleukin-1 (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Myd88 protein, mouse (NLM Chemicals)
KW  - TIRAP protein, mouse (NLM Chemicals)
KW  - TIRAP protein, human (NLM Chemicals)
KW  - Lipopolysaccharides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39025856
C2  - pmc:PMC11258287
DO  - DOI:10.1038/s41467-024-50341-w
UR  - https://inrepo02.dkfz.de/record/291762
ER  -