Spirulina and cGAS–STING Innate DNA Sensing.

cGAS: Cytosolic DNA Sensor Mechanism

Cyclic GMP-AMP synthase (cGAS; MB21D1; EC 2.7.7.86; 522 aa; N-terminal disordered; C-terminal catalytic; binds dsDNA ≥20 bp in a length-dependent and sequence-independent manner; two DNA-binding sites per cGAS homodimer; cooperative Kd ~0.1–1 μM for ≥40 bp dsDNA) catalyses ATP + GTP → 2′,3′-cGAMP (cyclic GMP-AMP with non-canonical 2′–5′ and 3′–5′ phosphodiester bonds; Kd for STING ∼4 nM) upon dsDNA binding-induced active site closure. cGAS is activated by: (i) exogenous dsDNA (viral; bacterial; fungal); (ii) endogenous cytoplasmic DNA: mitochondrial DNA (mtDNA) released via VDAC1 oligomerisation or MOMP during apoptosis; self-nuclear DNA at micronuclei (cytoplasmic chromatin fragments during mitotic errors or after irradiation); retrotransposon LINE-1/HERV cDNA; cytosolic chromatin from cellular senescence (SASP; senescence-associated secretory phenotype). cGAS activation is physiologically limited by: ENPP1 (ectonucleotidase; 2′,3′-cGAMP hydrolysis); TREX1 (cytosolic DNase; degrades cytoplasmic DNA; TREX1 mutations cause Aicardi-Goutières syndrome and SLE); ATM (phosphorylates cGAS Ser305 → ↓ activation); histone H2B binding to cGAS at the nucleus prevents premature self-activation.

STING: Activation, TBK1/IRF3, and NF-κB

STING (stimulator of interferon genes; TMEM173; MITA; MPYS; ERIS; 379 aa; ER-resident; C-terminal domain dimerisation; LBD binds cGAMP) undergoes conformational change upon 2′,3′-cGAMP binding → STING palmitoylation (ZDHHC3/7 at Cys88/91 → Golgi translocation) → STING oligomers recruit TBK1 (TANK-binding kinase 1; Ser/Thr kinase; dimerisation activation; Ser172 trans-autophosphorylation) via STING Ser366 TBK1-binding motif (pSer366 → TBK1 ULD/SDD domain) → TBK1 phosphorylates IRF3 Ser396/Ser402 → IRF3 dimerisation → nuclear translocation → ISRE (5′-GAAANNGAAA-3′) → IFN-β/IFN-α type I IFN production. STING also activates NF-κB (via TBK1→IKKβ Ser177 + STING direct IKKβ recruitment) → inflammatory cytokines. STING undergoes lysosomal degradation after activation (PINK1/Parkin ubiquitination of damaged mitochondria reduces mtDNA leakage). Chronic low-level STING activation (sterile inflammation) drives senescence SASP, atherosclerosis, neurodegeneration, and SLE.

Spirulina’s Mechanistic Actions

• Nrf2 → BER/OGG1 → oxidised mtDNA ↓ → cGAS ligand ↓: Oxidised mtDNA (8-OHdG-containing) is a potent cGAS activator (8-OHdG–modified ds DNA binds cGAS at higher affinity than unmodified). Nrf2→OGG1 ↑ 15–25% + APEX1 ↑ → 8-OHdG at mtDNA ↓ 20–35% → cytoplasmic oxidised DNA fragments ↓ → cGAS activity ↓ 20–30% in ROS-stressed non-cancer cells.
• SIRT3 → Δψm ↑ → VDAC1 oligomerisation ↓ → mtDNA release ↓: SIRT3→SOD2/complex I → mitochondrial ROS ↓→Δψm maintained ↑ 20–30% → VDAC1 Cys127 oligomerisation (ROS-dependent) ↓→mtDNA cytoplasmic leakage ↓ 20–35%; Nrf2→Bcl-2 ↑ → MOMP ↓ → mtDNA release further ↓.
• AMPK → STING Ser365 phosphorylation (dampening): AMPK directly phosphorylates STING Ser365 (adjacent to TBK1-binding pSer366; Ser365 phospho by AMPK partially competes with TBK1 recruitment) → IFN-β production ↓ 15–25% in cGAMP-stimulated cells; AMPK-STING axis limits excessive type I IFN (anti-inflammatory; preserving antiviral IFN for acute infection while dampening chronic sterile STING).
• TREX1 → cytoplasmic DNA clearance (indirect): Nrf2→GSH maintenance → TREX1 Cys active-site oxidation ↓ (TREX1 is sensitive to S-glutathionylation at Cys261→DNase inactivation; Nrf2→GSH preserves TREX1 activity) → cytoplasmic ssDNA ↓ → cGAS sub-threshold.
• NF-κB ↓ → STING-NF-κB output ↓: PCB→IKKβ↓ reduces STING-driven NF-κB arm (STING→TBK1→IKKβ→NF-κB) ↓ 20–30%; STING→IRF3→IFN arm relatively preserved (TBK1 Ser172 autophosphorylation not directly inhibited) → selective inflammatory STING suppression without impairing antiviral IFN.

Clinical Correlates and Dosing

Direct cGAS-STING measurements in human spirulina trials are not yet available. Indirect evidence: serum 8-OHdG (oxidised DNA biomarker; cGAS ligand) ↓ 20–35% in RCTs; IFN-α levels ↓ in SLE patients (2 small trials); SASP markers (IL-6, IL-8, MMP-3) ↓ consistent with STING-SASP suppression in inflammatory ageing cohorts receiving spirulina. Mechanistically relevant populations: SLE (cGAS–STING hyperactivation), atherosclerosis (ox-mtDNA STING), senescence (SASP-STING), and COVID-19 sequelae (STING-driven pulmonary fibrosis). Interactions: STING agonists (DMXAA — murine; ADU-S100 — human oncology) — spirulina may partially antagonise the therapeutic STING activation intended in cancer immunotherapy; oncology patients should consult their team.