Mislocalization of the interferon inducible protein IFI16 by environmental insults: Implications in autoimmunity

• IFI16 is discovered as circulatory protein in the sera of systemic autoimmune patients.
• Human cytomegalovirus has evolved mechanisms to mislocalize and hijack IFI16, trapping it within mature virions to counteract host viral restriction.
• IFI16, mature IL-1β, IL-18 and IL-33 are sorted and released into exosomal compartments during IFI16 mediated inflammasome signaling.
• IFI16 is a “danger signal” in the extracellular environment.

The nuclear DNA sensor IFI16, a member of PYHIN family of proteins, was previously studied for its role in cell cycle regulation, tumor suppression, apoptosis and DNA damage signaling. Autoantibodies against IFI16 are prevalent in the sera of patients with systemic autoimmunity, thus depicting physiological significance as an autoantigen. At present, the nuclear IFI16 protein has been thoroughly investigated for its role as an innate immune sensor involved in inflammasome signaling and viral restriction. While the sub-cellular localization of IFI16 during such events has been known, very little knowledge about its presence and significance in the extracellular space is available. Recently our group has discovered the presence of circulating IFI16 in the sera from systemic autoimmune patients indicating that in this setting it may be mislocalized form its nuclear site and secreted in the extracellular milieu. In this review, we will discuss the leakage of endogenous IFI16 that has been experimentally proved using in vivo and in vitro models. Also we will comment on the significance of mislocalized inflammasome components in the extracellular space and how it can be responsible for chronic inflammation.