ArticleProceedings of the National Academy of Sciences of the United States of America2014
Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 150 citations in OpenAlex.
- Trial
- Selenoproteins: Minute yet vital players governing cellular fate.Genes & diseases · 2026Review
- Palmitoylation-dependent regulation of innate and adaptive immunity: molecular insights and translational opportunities.Cellular & molecular biology letters · 2026Review
- Between Deficiency and Excess: The Dual Role of Selected Dietary Supplements in Immune Health.Cureus · 2026Review
- ZDHHC-Mediated Protein S-Palmitoylation in Cancer: Epigenetic Interfaces, Structural Logic and Therapeutic Targeting.International journal of medical sciences · 2026Review
- Article
- β-Carotene liposome-based responsive hydrogel inhibits palmitoylation to restore intracellular calcium homeostasis for effective periodontitis treatment.Journal of nanobiotechnology · 2025Article
- ZDHHC21-driven S-palmitoylation of Themis regulates the function of T cells and maintains homeostatic balance.Cell communication and signaling : CCS · 2025Article
- Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.Science advances · 2025Review
- Palmitoylation: an emerging therapeutic target bridging physiology and disease.Cellular & molecular biology letters · 2025Review
- Palmitic acid and palmitoylation in cancer: Understanding, insights, and challenges.Innovation (Cambridge (Mass.)) · 2025Review
- Selenoprotein K Is a Peripheral ER Membrane Protein.Biochemistry · 2025Article
- Selenoprotein K Confers Protection against Iron Dyshomeostasis-Related Neurotoxicity by Regulating the Palmitoylation of TfR-1.Journal of agricultural and food chemistry · 2025Article
- Role of selenium in the pathophysiology of cardiorenal anaemia syndrome.ESC heart failure · 2025Review
- Selenoprotein K at the intersection of cellular pathways.Archives of biochemistry and biophysics · 2025Review
- Advances in targeting protein S-palmitoylation in tumor immunity and therapy.Frontiers in oncology · 2025Review
- S-acylation of CaChronic diseases and translational medicine · 2024Review
- Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming.Journal of experimental & clinical cancer research : CR · 2024Article
- zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function.Acta pharmacologica Sinica · 2024Article
- Protein lipidation in health and disease: molecular basis, physiological function and pathological implication.Signal transduction and targeted therapy · 2024Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Calcium (Ca(2+)) is a secondary messenger in cells and Ca(2+) flux initiated from endoplasmic reticulum (ER) stores via inositol 1,4,5-triphosphate (IP3) binding to the IP3 receptor (IP3R) is particularly important for the activation and function of immune cells. Previous studies demonstrated that genetic deletion of selenoprotein K (Selk) led to decreased Ca(2+) flux in a variety of immune cells and impaired immunity, but the mechanism was unclear. Here we show that Selk deficiency does not affect receptor-induced IP3 production, but Selk deficiency through genetic deletion or low selenium in culture media leads to low expression of the IP3R due to a defect in IP3R palmitoylation. Bioinformatic analysis of the DHHC (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) family of enzymes that catalyze protein palmitoylation revealed that one member, DHHC6, contains a predicted Src-homology 3 (SH3) domain and DHHC6 is localized to the ER membrane. Because Selk is also an ER membrane protein and contains an SH3 binding domain, immunofluorescence and coimmunoprecipitation experiments were conducted and revealed DHHC6/Selk interactions in the ER membrane that depended on SH3/SH3 binding domain interactions. DHHC6 knockdown using shRNA in stably transfected cell lines led to decreased expression of the IP3R and impaired IP3R-dependent Ca(2+) flux. Mass spectrophotometric and bioinformatic analyses of the IP3R protein identified two palmitoylated cysteine residues and another potentially palmitoylated cysteine, and mutation of these three cysteines to alanines resulted in decreased IP3R palmitoylation and function. These findings reveal IP3R palmitoylation as a critical regulator of Ca(2+) flux in immune cells and define a previously unidentified DHHC/Selk complex responsible for this process.
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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.