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STING-dependent cytosolic DNA sensor pathways regulate NKG2D ligand expression.

Le Bert N, Lam AR, Ho SS, Shen YJ, Liu MM, Gasser S - Oncoimmunology (2014)

Bottom Line: The DNA damage response (DDR) upregulates the expression of NKG2D ligands (NKG2DLs).(1,2) We have recently reported that the DDR also induces the presence of cytosolic DNA in B-cell lymphoma cells, which leads to the activation of STING-dependent cytosolic DNA sensor pathways and the expression of RAE-1 ligands for NKG2D.(3.)

View Article: PubMed Central - PubMed

Affiliation: Immunology Programme; Centre of Life Sciences; Department of Microbiology; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.

ABSTRACT
The DNA damage response (DDR) upregulates the expression of NKG2D ligands (NKG2DLs).(1,2) We have recently reported that the DDR also induces the presence of cytosolic DNA in B-cell lymphoma cells, which leads to the activation of STING-dependent cytosolic DNA sensor pathways and the expression of RAE-1 ligands for NKG2D.(3.)

No MeSH data available.


Related in: MedlinePlus

Figure 1. STING-dependent DNA sensor pathways induce the expression of ligands for NKG2D in B-cell lymphoma cells. Damaged DNA and the ensuing DNA damage response lead to the presence of single-stranded and double-stranded DNA in the cytosol. Cytosolic DNA activates STING-dependent DNA sensor pathways, which induce the expression of NKG2D ligands and potentially other immunomodulatory molecules.
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Figure 1: Figure 1. STING-dependent DNA sensor pathways induce the expression of ligands for NKG2D in B-cell lymphoma cells. Damaged DNA and the ensuing DNA damage response lead to the presence of single-stranded and double-stranded DNA in the cytosol. Cytosolic DNA activates STING-dependent DNA sensor pathways, which induce the expression of NKG2D ligands and potentially other immunomodulatory molecules.

Mentions: The DDR also plays an important role in the immune surveillance of cancer.1 We recently reported that the DDR induces the expression of NKG2DLs through the activation of Sting-dependent cytosolic DNA sensor pathways.3 Strikingly, our data suggest that DNA damage in lymphoma cells leads to the presence of single-stranded (ss) and double-stranded (ds) DNA in the cytosol (Fig. 1). It is conceivable that cytosolic DNA is released by dysfunctional mitochondria upon DNA damage or generated during repair of damaged genomic DNA. Inhibition of ATM and ATR, which are mostly nuclear proteins, led to the disappearance of cytosolic DNA indicating that nuclear DNA repair pathways are required for the generation of cytosolic DNA. The DDR is constitutively active in many tumor cells possibly due to oncogene-induced replication stress resulting in collapsed replication forks and associated DNA damage.6 DDR-dependent homologous recombination plays an important role in restarting collapsed forks. Deletion of genomic DNA might result from homologous recombination between dispersed homologous sequences. In summary, our data suggest that nuclear DNA damage results in the presence of DNA in the cytosol of lymphoma cells.


STING-dependent cytosolic DNA sensor pathways regulate NKG2D ligand expression.

Le Bert N, Lam AR, Ho SS, Shen YJ, Liu MM, Gasser S - Oncoimmunology (2014)

Figure 1. STING-dependent DNA sensor pathways induce the expression of ligands for NKG2D in B-cell lymphoma cells. Damaged DNA and the ensuing DNA damage response lead to the presence of single-stranded and double-stranded DNA in the cytosol. Cytosolic DNA activates STING-dependent DNA sensor pathways, which induce the expression of NKG2D ligands and potentially other immunomodulatory molecules.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126837&req=5

Figure 1: Figure 1. STING-dependent DNA sensor pathways induce the expression of ligands for NKG2D in B-cell lymphoma cells. Damaged DNA and the ensuing DNA damage response lead to the presence of single-stranded and double-stranded DNA in the cytosol. Cytosolic DNA activates STING-dependent DNA sensor pathways, which induce the expression of NKG2D ligands and potentially other immunomodulatory molecules.
Mentions: The DDR also plays an important role in the immune surveillance of cancer.1 We recently reported that the DDR induces the expression of NKG2DLs through the activation of Sting-dependent cytosolic DNA sensor pathways.3 Strikingly, our data suggest that DNA damage in lymphoma cells leads to the presence of single-stranded (ss) and double-stranded (ds) DNA in the cytosol (Fig. 1). It is conceivable that cytosolic DNA is released by dysfunctional mitochondria upon DNA damage or generated during repair of damaged genomic DNA. Inhibition of ATM and ATR, which are mostly nuclear proteins, led to the disappearance of cytosolic DNA indicating that nuclear DNA repair pathways are required for the generation of cytosolic DNA. The DDR is constitutively active in many tumor cells possibly due to oncogene-induced replication stress resulting in collapsed replication forks and associated DNA damage.6 DDR-dependent homologous recombination plays an important role in restarting collapsed forks. Deletion of genomic DNA might result from homologous recombination between dispersed homologous sequences. In summary, our data suggest that nuclear DNA damage results in the presence of DNA in the cytosol of lymphoma cells.

Bottom Line: The DNA damage response (DDR) upregulates the expression of NKG2D ligands (NKG2DLs).(1,2) We have recently reported that the DDR also induces the presence of cytosolic DNA in B-cell lymphoma cells, which leads to the activation of STING-dependent cytosolic DNA sensor pathways and the expression of RAE-1 ligands for NKG2D.(3.)

View Article: PubMed Central - PubMed

Affiliation: Immunology Programme; Centre of Life Sciences; Department of Microbiology; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.

ABSTRACT
The DNA damage response (DDR) upregulates the expression of NKG2D ligands (NKG2DLs).(1,2) We have recently reported that the DDR also induces the presence of cytosolic DNA in B-cell lymphoma cells, which leads to the activation of STING-dependent cytosolic DNA sensor pathways and the expression of RAE-1 ligands for NKG2D.(3.)

No MeSH data available.


Related in: MedlinePlus