SELENOK

availability_state

Insufficient or absent SELENOK function; the reported phenotype comes from SELENOK-null mice.

experimental_scope

SELENOK loss-of-function animal model and supplied biochemical mechanism, including T-cell context.

limitations

Dietary selenium restriction is not proven equivalent to SELENOK knockout. No selenium concentration is mapped to this phenotype, and this scenario does not invert every downstream normal-path arrow.

trigger_kind

machinery_impairment

Selenium in immune cells · lines 18–20

Selenium immune-cell mechanism draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate

Selenium: the molecular cascade · lines 139–139

Selenium molecular cascade draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

**SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.**

availability_state

Insufficient or absent SELENOK function; the reported phenotype comes from SELENOK-null mice.

experimental_scope

SELENOK loss-of-function animal model and supplied biochemical mechanism, including T-cell context.

limitations

Dietary selenium restriction is not proven equivalent to SELENOK knockout. No selenium concentration is mapped to this phenotype, and this scenario does not invert every downstream normal-path arrow.

trigger_kind

machinery_impairment

Selenium in immune cells · lines 22–28

Selenium immune-cell mechanism draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

3. ZDHHC6 palmitoylates: • IP3R (all three isoforms) • calnexin • itself (autopalmitoylation) 4. Palmitoylated IP3R = stable, correctly localized, functional channel Non-palmitoylated IP3R = degraded / non-functional

Selenium: the molecular cascade · lines 139–139

Selenium molecular cascade draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

**SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.**

availability_state

Insufficient or absent SELENOK function; the reported phenotype comes from SELENOK-null mice.

experimental_scope

SELENOK loss-of-function animal model and supplied biochemical mechanism, including T-cell context.

limitations

Dietary selenium restriction is not proven equivalent to SELENOK knockout. No selenium concentration is mapped to this phenotype, and this scenario does not invert every downstream normal-path arrow.

trigger_kind

machinery_impairment

Selenium in immune cells · lines 27–32

Selenium immune-cell mechanism draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

4. Palmitoylated IP3R = stable, correctly localized, functional channel Non-palmitoylated IP3R = degraded / non-functional 5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion

Selenium in immune cells · lines 42–42

Selenium immune-cell mechanism draft · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

**Kill SELENOK and you lose step 4.** The phenotype in SELENOK⁻/⁻ mice is exactly what the chain predicts: blunted Ca²⁺ flux in **T cells, B cells, neutrophils, and macrophages**; reduced TCR-driven proliferation; impaired chemotaxis; reduced IL-2.

evidence_span

{"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"}

experimental_model

Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays

exposure

Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants

limitations

Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mouse immune cells and mammalian cell models

plain_language

Two separately identifiable proteins cooperate in maintaining the receptor.

primary_references

[ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

tissue_or_cell_type

ER-associated IP3 receptor machinery

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1094–1105

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays · source_derived_draft · unverified_draft

### ino-selk-dhhc6 SELENOK and DHHC6 interacted at the ER membrane through SH3-related binding interactions. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two separately identifiable proteins cooperate in maintaining the receptor. organism: Mouse immune cells and mammalian cell models tissue_or_cell_type: ER-associated IP3 receptor machinery experimental_model: Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays limitations: Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure. exposure: Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants evidence_span: {"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"} [ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"}

experimental_model

Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays

exposure

Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants

limitations

Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mouse immune cells and mammalian cell models

plain_language

Failure downstream of IP3 does not automatically mean too little inositol or too little IP3.

primary_references

[ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

tissue_or_cell_type

ER-associated IP3 receptor machinery

trigger_kind

machinery_impairment Imported condition classification; unverified.

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1081–1092

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays · source_derived_draft · unverified_draft

### ino-selk-message-intact SELENOK deficiency did not impair receptor-induced IP3 production in the reported experiments. Condition category: machinery_impairment nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Failure downstream of IP3 does not automatically mean too little inositol or too little IP3. organism: Mouse immune cells and mammalian cell models tissue_or_cell_type: ER-associated IP3 receptor machinery experimental_model: Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays limitations: Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure. exposure: Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants evidence_span: {"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"} [ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

Selenium corrections and deep dive · lines 446–448

Selenium correction and deep-dive draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

**4. The PE circuit.** SELENOI **makes** PE. GPX4 **protects** PE. SELENOK **enables palmitoylation of IP3R**, which controls the Ca²⁺ flux that drives lipid peroxidation. Three selenoproteins, three different verbs, one lipid. SELENOI mutations cause **SPG81 spastic paraplegia**; GPX4 loss causes **interneuron death**. Both neurological, both PE. Nobody has assayed them as one circuit. **If I were hunting for something undiscovered, this is where I'd put the money.**

cell_type

· T cell

evidence_scope

Source-derived draft; primary-source verification required

organism

· Human

Selenium in immune cells · lines 11–20

Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

# I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate

Selenium: the molecular cascade · lines 135–143

Selenium molecular cascade draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

**SELENOO** — the strangest protein in the set. Its bacterial ortholog **SelO** looks exactly like a protein kinase but binds ATP **flipped backwards** in the pocket, so it transfers **AMP instead of phosphate**. It's an **AMPylase**, activated by oxidative stress, AMPylating GAPDH and other redox enzymes. A pseudokinase that runs in reverse. Human SELENOO is mitochondrial and largely uncharacterized. **MSRB1 (SELENOR)** — redox control of the cytoskeleton. **MICAL1/2** oxidizes actin **Met44 and Met47** to the R-sulfoxide → actin depolymerizes. MSRB1 reduces it back → repolymerization. In macrophages this gates phagocytic cup formation. **Selenium is a direct rheostat on actin dynamics.** Almost nobody knows this. **SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.** **SELENOI (EPT1)** — the only selenoprotein with **zero redox function**. It's an ethanolamine phosphotransferase making phosphatidylethanolamine. Mutations → hereditary spastic paraplegia **SPG81**. (And PE is exactly the lipid GPX4 protects. There's a loop there worth pulling on.) **SELENON** — ER membrane, regulates **RyR1** redox state and SERCA2b. Mutations → SEPN1-related myopathy / rigid spine syndrome.

cell_type

· T cell

evidence_scope

Source-derived draft; primary-source verification required

organism

· Human

Selenium in immune cells · lines 11–20

Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

# I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"}

experimental_model

Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays

exposure

Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants

limitations

Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mouse immune cells and mammalian cell models

plain_language

The cell may still make the message but lose a properly maintained receptor.

primary_references

[ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

tissue_or_cell_type

ER-associated IP3 receptor machinery

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1068–1079

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays · source_derived_draft · unverified_draft

### ino-selenium-receptor Low-selenium culture conditions were associated with defective IP3R palmitoylation and reduced receptor expression in the SELENOK study. Condition category: nutrient_deficiency nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cell may still make the message but lose a properly maintained receptor. organism: Mouse immune cells and mammalian cell models tissue_or_cell_type: ER-associated IP3 receptor machinery experimental_model: Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays limitations: Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure. exposure: Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants evidence_span: {"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"} [ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111