Nuclear envelope proteins restrain the immune protein STING; partially inhibiting STING extended survival in mice with progeria, a disease of accelerated aging
Nuclear envelope proteins restrain the immune protein STING; partially inhibiting STING extended survival in mice with progeria, a disease of accelerated aging
On August 19, Nature Communications published a paper describing a mechanism that restrains STING, an innate immune protein that initiates inflammatory signaling. In two mouse models of progeria, the experimental compound H-151 reduced signs of tissue aging and increased median lifespan.
DNA normally remains inside the cell nucleus. When the nuclear envelope is damaged, chromatin fragments, which consist of DNA and associated proteins, enter the cytoplasm. The immune protein cGAS detects these fragments and activates STING. A brief alarm signal helps the cell respond to damage, whereas a sustained signal maintains inflammation and cellular senescence.
The authors first asked whether the enzyme CK2α connects nuclear envelope damage to this alarm response. They identified CK2α among the proteins located near STING and confirmed that the two proteins interact directly, both in cells and in vitro. CK2α adds a phosphate group to STING at Ser366, while lamins A/C, proteins in the inner layer of the nuclear envelope, keep both proteins close together. Once STING receives this phosphate group, the cell removes it more rapidly, allowing the inflammatory signal to subside sooner.
When the authors replaced Ser366, CK2α still interacted with STING but could no longer add the phosphate group. This experiment distinguished simple proximity between the proteins from the mechanism through which they act. The researchers then deleted Ck2α in myeloid cells, a group of immune cells that includes macrophages. STING accumulated in the mice, which lost hair, developed impaired cardiac function, and had lower bone density; median lifespan in males fell from 733,5 to 502 days.
In the progeria model, H-151 increased median lifespan from 122 to 149 days in males and from 120 to 156 days in females; tissues contained fewer cells with signs of senescence, and bone density increased. Complete genetic deletion of STING produced a smaller survival benefit in this model. In two telomerase-deficient mouse lines, deleting STING likewise neither improved tissue condition nor extended lifespan.
The authors attribute the advantage of H-151 to the ability to adjust its dose and discontinue treatment. Their data indicate that the permanent absence of STING affects tissue macrophages and immune system homeostasis.