Abstract
SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the ten past years, SHIP-1 has been described as an important regulator of immune functions. Here, we characterize a new inhibitory function for SHIP-1 in NOD2 signaling. NOD2 is a crucial cytoplasmic bacterial sensor that activates proinflammatory and antimicrobial responses upon bacterial invasion. We observed that SHIP-1 decreases NOD2-induced NF-κB activation in macrophages. This negative regulation relies on its interaction with XIAP. Indeed, we observed that XIAP is an essential mediator of the NOD2 signaling pathway that enables proper NF-κB activation in macrophages. Upon NOD2 activation, SHIP-1 C-terminal proline rich domain (PRD) interacts with XIAP, thereby disturbing the interaction between XIAP and RIP2 in order to decrease NF-κB signaling.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cell Line, Tumor
-
Down-Regulation
-
Epithelial Cells / cytology
-
Gene Expression Regulation
-
Humans
-
Immune System
-
Inflammation
-
Inositol Polyphosphate 5-Phosphatases
-
Macrophages / cytology
-
Macrophages / metabolism
-
Models, Biological
-
Monocytes / cytology
-
NF-kappa B / metabolism*
-
Nod2 Signaling Adaptor Protein / metabolism*
-
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
-
Phosphoric Monoester Hydrolases / metabolism*
-
Protein Structure, Tertiary
-
Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism*
-
Signal Transduction
-
X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
-
NF-kappa B
-
NOD2 protein, human
-
Nod2 Signaling Adaptor Protein
-
X-Linked Inhibitor of Apoptosis Protein
-
XIAP protein, human
-
RIPK2 protein, human
-
Receptor-Interacting Protein Serine-Threonine Kinase 2
-
Phosphoric Monoester Hydrolases
-
Inositol Polyphosphate 5-Phosphatases
-
INPP5D protein, human
-
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases