The researchers found that the two proteins showed inhibitory activities when bound to genes involved in inflammation.
Specifically, SIX1 and SIX2 appeared to dampen the body’s immune response to prevent damage associated with a potentially life-threatening condition called a cytokine storm, which can occur in chronic inflammatory conditions.
“A cytokine storm can occur when the body’s immune cells and activators (cytokines) show an overresponse to a health threat such as the flu,” he explained.
An experiment with transgenic mice found that expression of SIX1 in adulthood conferred near-complete recovery following exposure to a toxin released by gram-negative bacteria that can set off a cytokine storm.
The two SIX proteins seem to dampen the response of the so-called noncanonical NF-κB pathway, a signaling cascade that is instrumental in the development of the lymph organs, the maturation of the immune system’s antibody-producing B cells, and the development of bone cells.
The same pathway is involved in the body’s immune defense in adulthood.
The studies, which initially focused on bacteria and viruses, also shed light on mechanisms of cancer cell resistance to drug treatment, Dr. Alto said.
In one series of experiments, the team found that cancer cells derived from patients with treatment-resistant non-small cell lung cancer expressed high levels of the SIX1 and SIX2 proteins.
The scientists used the CRISPR-Cas9 gene-editing technology to remove the genes that produce those two proteins, making the cancer cells dramatically more sensitive to a promising drug class called SMAC mimetics.
“In summary, we have established that SIX family transcription factors function as immunological gatekeepers, regulating the activity of inflammatory genes in response to noncanonical NF-κB pathway activation,” he said.
“These findings indicate that disruption of this pathway could have important consequences for the pathogenesis of human disease, including cancer.”
More information: Zixu Liu et al, A NIK–SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB, Nature(2019). DOI: 10.1038/s41586-019-1041-6
Provided by UT Southwestern Medical Center
