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The citrullinating enzyme PADI4 governs progenitor cell proliferation and translation in developing hair follicles

ABSTRACT: Posttranslational protein modifications have emerged as a mechanism regulating progenitor cell state transitions during tissue formation. Herein, we exploit the stereotyped hair follicle development to delineate the function of PADI4; an enzyme converting peptidylarginine to citrulline. Single cell-sequencing places Padi4 in both progenitor and differentiated hair lineage cells and indicate that PADI4 acts to repress transcription during hair follicle development. We establish PADI4 as a negative regulator of proliferation, acting on LEF1-positive hair shaft committed progenitor cells. Mechanistically, PADI4 citrullinates proteins associated with mRNA-processing and ribosomal biogenesis, and lack of PADI4 promotes protein synthesis and rRNA transcription in vivo. Characterizing key translational effectors, we demonstrate that PADI4 citrullinates the translational repressor 4E-BP1 and reveal a crosstalk between PADI4 activity and 4E-BP1 phosphorylation. This work sheds new light on how posttranslational modifications impact progenitor cell states and tissue formation.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Keratinocyte, Skin

DISEASE(S): Disease Free

SUBMITTER: Maria Genander

LAB HEAD: Maria Genander

PROVIDER: PXD064137 | Pride | 2025-07-28

REPOSITORIES: Pride

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			Action	DRS
	20200219_L1_01_Kim_TMT_F1.raw	Raw
	20200219_L1_02_Kim_TMT_F2.raw	Raw
	20200219_L1_03_Kim_TMT_F3.raw	Raw
	20200219_L1_04_Kim_TMT_F4.raw	Raw
	20200219_L1_05_Kim_TMT_F5.raw	Raw

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Single-cell sequencing WT and PADI4 cKO skin, P1

Project description:Tissue formation requires a coordinated balance of progenitor cell proliferation and differentiation. Posttranslational protein modifications have emerged as a mechanism utilized to regulate progenitor cell state transitions. Herein, we exploit the well characterized and stereotyped hair follicle development to delineate the function of PADI4; an enzyme converting peptidylarginine to citrulline. Single cell-sequencing places Padi4 in both progenitor and differentiated hair lineage cells during hair follicle development. We show that the absence of PADI4 induces gene expression across hair follicle cell clusters, suggesting that PADI4 acts to negatively impact transcription. In addition, we establish PADI4 as a negative regulator of proliferation, acting of LEF1-positive hair shaft committed progenitor cells. Mechanistically, PADI4 citrullinates proteins associated with mRNA-processing and ribosomal biogenesis, and lack of PADI4 promotes protein synthesis and rRNA transcription in vivo, in both hair follicle progenitor and committed lineage cells. Characterizing key translational effectors, we demonstrate that PADI4 interacts with 4E-BP1 and reveal a crosstalk between PADI4 activity and 4E-BP1 phosphorylation. We report that PADI4 contributes to hair follicle development by repressing progenitor cell proliferation and translational activity. This work sheds new light on how posttranslational modifications impact progenitor cell states and tissue formation.

2025-07-28 | GSE288124 | GEO

Project description:Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) inhibits cap-dependent translation in eukaryotes by competing with eIF4G for an interaction with eIF4E. Phos-phorylation at Ser-83 of 4E-BP1 occurs during mitosis through the activity of cyclin-dependent kinase 1 (CDK1)/cyclin B rather than through canonical mTOR kinase activity. Here, we investi-gated the interaction of eIF4E with 4E-BP1 or eIF4G during interphase and mitosis. We observed that 4E-BP1 and eIF4G bind eIF4E at similar levels during interphase and mitosis. The most highly phosphorylated mitotic 4E-BP1 isoform (δ) did not interact with eIF4E, whereas a distinct 4E-BP1 phospho-isoform, EB-γ—phosphorylated at Thr-70, Ser-83, and Ser-101—bound to eIF4E during mitosis. Two-dimensional gel electropho-retic analysis corroborated the identity of the phosphorylation marks on the eIF4E-bound 4E-BP1 isoforms and uncovered a population of phosphorylated 4E-BP1 molecules lacking Thr-37/Thr-46–priming phosphorylation. Moreover, proximity ligation assays for phospho–4E-BP1 and eIF4E revealed different in situ interactions during interphase and mitosis. The eIF4E:eIF4G interaction was not inhibited, but rather increased in mitotic cells, consistent with active translation initiation during mitosis. Phospho-defective substitution of 4E-BP1 at Ser-83 did not change global translation or individual mRNA translation profiles as measured by single-cell nascent protein synthesis and eIF4G RNA-immunoprecipitation sequencing. Mitotic 5’-terminal oligopyrimidine RNA translation was active and, unlike interphase translation, resistant to mTOR inhibition. Our findings reveal the phosphorylation profiles of 4E-BP1 isoforms and their interactions with eIF4E throughout the cell cycle and indicate that 4E-BP1 does not specifically inhibit translation initiation during mitosis.

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Chromosome 8 gain drives cancer progression by hijacking the translation factor 4E-BP1 sensitizing for targeted CDK4/6 inhibition

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Chromosome 8 gain drives cancer progression by hijacking the translation factor 4E-BP1 sensitizing for targeted CDK4/6 inhibition [II]

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Project description:Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs accelerates cellular senescence, compromises mitochondrial respiration and increases mitochondrial ROS production. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of the complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These findings together demonstrate that 4E-BP1 functions as a geroprotector to alleviate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III and provide a new potential target to counteract human stem cell senescence.

2023-05-10 | PXD033301 | Pride

4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling

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Expression data from discodermolide sensitive and resistant cell lines

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4E-BP1-dependent translation in microglia controls mechanical hypersensitivity

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4E-BP1-dependent translation in microglia controls mechanical hypersensitivity

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