The PYRIN domain–only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses

Abstract

The innate immune system responds to infections and tissue damage by activating cytosolic sensory complexes called inflammasomes. Cytosolic DNA is sensed by AIM2-like receptors (ALRs) during bacterial and viral infections and in autoimmune diseases. Subsequently, recruitment of the adaptor protein ASC links ALRs to the activation of caspase-1. A controlled immune response is crucial for maintaining homeostasis, but ALR inflammasome regulation is poorly understood. Here, we identified the PYRIN domain (PYD)-only protein 3 (POP3), which competes with ASC for recruitment to ALRs, as an inhibitor of DNA virus-induced ALR inflammasome activation in vivo. Using a mouse model with macrophage-specific POP3 expression, the data emphasizes the importance of ALR inflammasome regulation in the monocytic/macrophage.

The emerging role of human PYHIN proteins in innate immunity: Implications for health and disease

“…The most recent addition to the PYHIN family is POP3 [3]. The gene encoding POP3 was recently shown to reside between PYHIN1 and IFI16 on the PYHIN locus (Fig.…”

“…POP3 lacks a HIN domain responsible for DNA binding, but possesses a PYD domain. As such, POP3 can strongly interact with the ALRs AIM2 and IFI16, likely modulating their roles in innate immunity [3].…”

“…An interesting mechanism of PYHIN regulation has recently been uncovered with the discovery of the newest member of the PYHIN family, POP3 [3]. POP3 lacks the HIN domain found in other PYHINs (Fig.…”

“…The 200 amino acid DNA binding HIN domain is classified into three subtypes, termed A, B and C, based on consensus motifs [8]. POP3, the most recent member of this gene cluster to be identified, lacks the HIN domains found in other PYHIN proteins [3].…”

“…AIM2 and POP3 are predominantly cytosolic proteins, while IFI16, MNDA and PYHIN1 are predominantly found in the nucleus owing to the presence of an N-terminal nuclear localisation sequence (NLS) [3,9]. However, other factors such as acetylation or the presence of stimulatory DNA (in the case of IFI16), or the onset of apoptosis (in the case of MNDA), can also influence their cellular localisation [10][11][12].…”