ArticleCell research2017
Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis.
Article in Cell research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 56 citations in OpenAlex.
- Dual itaconate delivery systems modulate macrophage Acod1-Hif-1α-glycolysis axis for immunotherapy of bioprosthetic heart valve calcification.Bioactive materials · 2026Article
- DNA co-recognition and pH dependent regulation mechanism of zinc finger domain and C-terminal basic region of CreA in Aspergillus.Archives of microbiology · 2026Article
- pH sensing and inflammation: linking acidic microenvironments to immune reprogramming.Frontiers in immunology · 2026Review
- Translational biomarkers of hypoxic brain injury uncovered in CSF secreting human choroid plexus organoids.Fluids and barriers of the CNS · 2025Article
- Androgen-Induced Lactic Acid Accumulation Contributes to the Apoptosis of Ovarian Granulosa Cells in Polycystic Ovary Syndrome Mice.Antioxidants (Basel, Switzerland) · 2025Article
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- Revolutionizing neural regeneration with smart responsive materials: Current insights and future prospects.Bioactive materials · 2025Review
- Control of Inflammatory Response by Tissue Microenvironment.bioRxiv : the preprint server for biology · 2025Article
- CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer.Nature communications · 2025Article
- Regulation of Glycolysis by SMAD5 in Glioma Cells: Implications for Tumor Growth and Apoptosis.Neurochemical research · 2025Article
- SMAD5 as a novel gene for familial pulmonary arterial hypertension.Clinical science (London, England : 1979) · 2025Article
- Low temperature increases adenovirus replication via intracellular alkalization.Frontiers in cellular and infection microbiology · 2025Article
- Layered Double Hydroxide Reshapes the Immune Microenvironment of Rheumatoid Arthritis through Small Mothers against Decapentaplegic 5.Biomaterials research · 2025Article
- Exploring Smad5: a review to pave the way for a deeper understanding of the pathobiology of common respiratory diseases.Molecular medicine (Cambridge, Mass.) · 2024Review
- Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.The Journal of biological chemistry · 2024Article
- Medium acidosis drives cardiac differentiation during mesendoderm cell fate specification from human pluripotent stem cells.Stem cell reports · 2024Article
- Associations between High Protein Intake, Linear Growth, and Stunting in Children and Adolescents: A Cross-Sectional Study.Nutrients · 2023Article
- Article
- pH sensing at the intersection of tissue homeostasis and inflammation.Trends in immunology · 2023Review
- Diminishing neuronal acidification by channelrhodopsins with low proton conduction.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
27 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Both environmental cues and intracellular bioenergetic states profoundly affect intracellular pH (pHi). How a cell responds to pHi changes to maintain bioenergetic homeostasis remains elusive. Here we show that Smad5, a well-characterized downstream component of bone morphogenetic protein (BMP) signaling responds to pHi changes. Cold, basic or hypertonic conditions increase pHi, which in turn dissociates protons from the charged amino acid clusters within the MH1 domain of Smad5, prompting its relocation from the nucleus to the cytoplasm. On the other hand, heat, acidic or hypotonic conditions decrease pHi, blocking the nuclear export of Smad5, and thus causing its nuclear accumulation. Active nucleocytoplasmic shuttling of Smad5 induced by environmental changes and pHi fluctuation is independent of BMP signaling, carboxyl terminus phosphorylation and Smad4. In addition, ablation of Smad5 causes chronic and irreversible dysregulation of cellular bioenergetic homeostasis and disrupted normal neural developmental processes as identified in a differentiation model of human pluripotent stem cells. Importantly, these metabolic and developmental deficits in Smad5-deficient cells could be rescued only by cytoplasmic Smad5. Cytoplasmic Smad5 physically interacts with hexokinase 1 and accelerates glycolysis. Together, our findings indicate that Smad5 acts as a pHi messenger and maintains the bioenergetic homeostasis of cells by regulating cytoplasmic metabolic machinery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.