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Microbial-ligand independent regulation of lymphpoiesis by NOD1

ABSTRACT: Aberrant differentiation of progenitor cells in the hematopoietic system is known to severely impact host immune responsiveness. Here we demonstrate that NOD1, a cytosolic innate sensor of bacterial peptidoglycan, also functions in murine hematopoietic cells as a major regulator of both the generation and differentiation of lymphoid progenitors as well as peripheral T lymphocyte homeostasis. We further show that NOD1 mediates these functions by facilitating STAT5 signaling downstream of hematopoietic cytokines. In steady-state, loss of NOD1 resulted in a modest but significant decrease in numbers of mature T, B and NK cells. During systemic protozoan infection, this defect was markedly enhanced leading to host mortality. Lack of functional NOD1 also impaired T-cell-dependent anti-tumor immunity while preventing colitis. These findings reveal that in addition to its classical role as a bacterial ligand receptor, NOD1 plays an important function in regulating adaptive immunity through interaction with a major host cytokine signaling pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE236485 | GEO | 2023/10/25

REPOSITORIES: GEO

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Immune surveillance of cellular homeostasis by NOD1/2 via sensing cytosolic sphingosine-1-phosphate (S1P)

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Zebrafish embryos microinjected with ptGFP1 (control group) or ptGFP1-NOD1 (NOD1 group)

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Peptidoglycan metabolite photoaffinity reporters reveal direct binding to intracellular pattern recognition receptors and Arf GTPases

Project description:Extensive structure-activity studies of iE-DAP and MDP have demonstrated their selective activation of NOD1- and NOD2-expressing cells, respectively. Nonetheless, the direct binding of iE-DAP and MDP to NOD1 and NOD2, respectively, as well as other proteins in mammalian cells has not been systematically investigated. To address the direct interaction of iE-DAP and MDP with NOD1 and NOD2 in living cells, we synthesized a series of peptidoglycan metabolite photoaffinity chemical reporters containing a diazirine for photocrosslinking in cells and an alkyne tag for bioorthogonal detection of covalently-labeled proteins. The analysis of these peptidoglycan metabolite photoaffinity reporters demonstrate that iE-DAP and MDP can directly bind to NOD1 and NOD2 in mammalian cells. The crosslinking of these peptidoglycan metabolite photoaffinity reporters only occur with active variants of NOD1 and NOD2. Beyond direct binding to NOD2, the active MDP photoaffinity reporter selectively crosslinked Arf GTPases in NOD2-expressing cells and did so most prominently with GTP-bound Arf6, revealing the Arf proteins as novel direct pattern recognition receptors. Additional labeling and co-precipitation experiments suggest that MDP induces a complex between NOD2 and GTP-Arf6. This study highlights the utility of peptidoglycan metabolite photoaffinity reporters for characterizing their direct binding to intracellular pattern recognition receptors and identifying unpredicted cellular cofactors. The applications of these microbial-specific metabolite reporters should enable the discovery of other receptors, transporters and regulatory enzymes in host cells and microbes.

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