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Schematic of human STING genetic variants and
their functional effect or disease association

STING knockin Dual Reporter Monocytes

THP1-Dual™ KI-STING cells belong to a collection of human monocytic reporter cells designed to study the effect of important STING variations in the cytosolic DNA sensing (CDS) pathway.

This reporter cell family was generated from the THP1-Dual™ KO-STING cell line. They harbor a biallelic knockout (KO) of the endogenous HAQ hSTING gene, which contains three single nucleotide substitutions (SNS): H71‑A230-R232-Q293. Additionally, they express two inducible reporter genes, allowing the simultaneous study of the NF-κB and IRF pathways, by monitoring the respective SEAP (secreted embryonic alkaline phosphatase) and Lucia luciferase activities in the cell supernatant.

Each cell line features a stable knock-in (KI) of one distinct human (h)STING variant:

R232 – variant (R71‑G230-R232-R293) is present in ~60% of the human population and therefore, considered the wild-type (WT) hSTING [2].
R232H – frequently occurring isoform in the human population (~14%) leading to a diminished response to CDNs (cyclic dinucleotides) [2].
V155M – gain-of-function (GOF) mutation causing constitutive STING activation and severe SAVI disease (STING-Associated Vasculopathy with onset in Infancy) [3].
N154S – GOF mutation causing constitutive STING activation and severe SAVI disease [3].
S162A – point mutation that renders hSTING highly sensitive to DMXAA, a potent tumor vascular disrupting agent in mice [1].

These gene variants (alleles and mutants) differ in their responsiveness to microbial CDNs leading to loss or gain of STING functionality (see figures and VDS). Therefore, they represent a powerful tool to further understand STING biology and its impact on human health [1-3].

Key features:

Verified KO of the endogenous hSTING gene
Stable KI of one particular hSTING variant
Distinct monitoring of NF-κB or IRF activation by assessing the SEAP and Lucia luciferase activities

Applications:

Defining the responsiveness of each hSTING variant to microbial CDNs
Screening for hSTING-variant specific agonists and antagonists (H-151)
Highlighting the impact of each genetic variation on the STING-dependent IRF and NF-kB responses.

References:

1. Gao P. et al., 2014. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Cell Reports. 8:1668-76.
2. Yi G. et al., 2013. Single nucleotide polymorphisms of human STING can affect the innate immune response to cyclic dinucleotides. PLOS One. 8:e77846.
3. Liu Y. et al., 2014. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 371:507-18

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