IFI16, or Interferon-inducible protein 16, is a protein found inside human cells. It plays a role in the body’s innate immune system, the first line of defense against harmful invaders. This protein helps the body recognize and respond to various threats, maintaining cellular balance.
How IFI16 Detects Threats
IFI16 functions primarily as a sensor for DNA, identifying genetic material that does not belong or is abnormal. It recognizes foreign double-stranded DNA (dsDNA) from sources such as viruses and bacteria, as well as aberrant self-DNA from damaged cells. This protein is located in both the nucleus and cytoplasm of cells, and its specific location can influence its sensing abilities.
In the nucleus, IFI16 can detect viral DNA, such as that from herpesviruses, and then relocate to the cytoplasm to activate signaling pathways. When IFI16 binds to foreign dsDNA, it does so in a sequence-independent manner.
IFI16 differentiates between host and foreign DNA by recognizing structural differences. While host DNA is tightly packaged with proteins into nucleosomes, foreign DNA may have longer stretches of “exposed” DNA between nucleosomes, which IFI16 can bind to. This ability to discriminate is important to prevent the immune system from attacking the body’s own tissues. Upon binding, IFI16 promotes the formation of nucleosomes on foreign DNA, but these are more spaced out than those on host DNA.
IFI16’s Role in Inflammation
Once IFI16 detects foreign or aberrant DNA, it initiates inflammatory responses by activating inflammasomes. Inflammasomes are multi-protein complexes that trigger inflammation and are responsible for processing and secreting pro-inflammatory cytokines. IFI16 can form an inflammasome complex, particularly in response to viral infection, by interacting with adaptor proteins like ASC (Apoptosis-associated speck-like protein containing a CARD) and procaspase-1.
This complex leads to the cleavage and activation of procaspase-1, which then processes immature forms of Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) into their active, mature forms. These mature cytokines are then secreted, acting as potent signaling molecules that promote inflammation. The activation of inflammasomes, including those involving IFI16, is a protective mechanism against infections, although excessive activation can lead to issues.
For instance, IFI16 has been shown to assemble an inflammasome containing ASC and procaspase-1 in the nucleus when sensing replicating DNA of herpesviruses. This complex can lead to the processing of pro-IL-1β. The activation of these inflammasomes and the subsequent release of IL-1β and IL-18 are important for initiating an immune response.
IFI16 and Human Health
The activity of IFI16 has broad implications for human health, particularly in autoimmune diseases and cancer. In autoimmune conditions such as systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS), dysregulated IFI16 activity can contribute to chronic inflammation and tissue damage. Autoantibodies against IFI16 have been detected in a significant percentage of patients with SLE and SS.
In Sjögren’s syndrome, anti-IFI16 antibodies are a prominent feature and are associated with markers of more severe disease. IFI16 protein levels are also found to be higher in the salivary glands of SS patients compared to healthy individuals. This suggests that elevated IFI16 expression in affected tissues may contribute to the ongoing immune response against the protein itself.
IFI16 also plays a complex role in cancer, sometimes acting as a tumor suppressor and at other times promoting tumor growth. As a tumor suppressor, IFI16 can interact with the p53 protein, known for its role in preventing cancer, and enhance its activity. This interaction can lead to increased p53 activation, which can then induce programmed cell death in cancer cells.
Conversely, IFI16 can paradoxically act as a pro-tumorigenic factor, promoting inflammation that supports tumor growth. While IFI16 overexpression can reduce tumor volume in some cancers, its expression in others has been linked to promoting cell growth and preventing cell death. This dual role highlights the intricate balance of IFI16’s functions within different cancer types and cellular environments.