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A Polyamine-mediated Posttranslational Modification Required for Macrophage Tissue Residency [RNA-Seq]

ABSTRACT: Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris. During tissue damage, however, bone marrow-derived monocytes enter tissue sites and differentiate into RTM, repairing the tissue and replenishing macrophages in the niche. Universal cell-intrinsic mechanisms that control the monocyte to RTM transition remain elusive. We investigated mice with myeloid cell deletions in deoxyhypusine synthase (DHPS), an enzyme that mediates the polyamine-dependent hypusine modification of the translation factor eIF5A, and found that DHPS is required for cell adhesion and signaling programs critical for RTMs. Without DHPS expression, immature tissue macrophages form, but RTM and associated homeostatic functions are lost. Thus, the polyamine-hypusine pathway is a global, tissue-agnostic program driving the differentiation trajectory of monocyte-derived macrophages into RTM.

ORGANISM(S): Mus musculus

PROVIDER: GSE290686 | GEO | 2026/01/15

REPOSITORIES: GEO

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A Polyamine-mediated Posttranslational Modification Required for Macrophage Tissue Residency [scRNA-seq]

Project description:Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris. During tissue damage, however, bone marrow-derived monocytes enter tissue sites and differentiate into RTM, repairing the tissue and replenishing macrophages in the niche. Universal cell-intrinsic mechanisms that control the monocyte to RTM transition remain elusive. We investigated mice with myeloid cell deletions in deoxyhypusine synthase (DHPS), an enzyme that mediates the polyamine-dependent hypusine modification of the translation factor eIF5A, and found that DHPS is required for cell adhesion and signaling programs critical for RTMs. Without DHPS expression, immature tissue macrophages form, but RTM and associated homeostatic functions are lost. Thus, the polyamine-hypusine pathway is a global, tissue-agnostic program driving the differentiation trajectory of monocyte-derived macrophages into RTM.

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Polyamine metabolism regulates the T cell epigenome through hypusination [RNA-seq]

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Project description:Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

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: Hypusine Biosynthesis in β Cells Links Polyamine Metabolism to Facultative Cellular Proliferation to Maintain Glucose Homeostasis

Project description:: Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

2021-09-08 | PXD015414 | Pride

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