IFI16 Acts as a Nuclear Pathogen Sensor to Induce the Inflammasome in Response to Kaposi Sarcoma-Associated Herpesvirus Infection

Abstract

SUMMARY Inflammasomes are cytoplasmic sensors of foreign molecules, including pathogens, and function to induce caspase-1 activation and IL-1β cytokine maturation. Whether such a mechanism exists in the nucleus and is effective against nuclear replicating pathogens is unknown. Nuclear replicating herpesvirus KSHV is associated with Kaposi Sarcoma, an angioproliferative tumor characterized by an inflammatory microenvironment including IL-1β. We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome. This complex was initially detected in the nucleus and subsequently in the peri-nuclear area. KSHV gene expression and/or latent KSHV genome is required for inflammasome activation and IFI16 colocalizes with the KSHV genome in the infected cell nucleus. Caspase-1 activation by KSHV was reduced by IFI16 and ASC silencing. Our studies reveal IFI16 as a nuclear pathogen sensor and demonstrate that the inflammasome also functions in the nucleus.

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

“…As with AIM2, the sequence independent DNA binding by IFI16 is achieved by electrostatic attraction between positively charged HIN domain residues and the dsDNA sugar phosphate backbone [41]. This allows IFI16 to detect dsDNA from many sources including Kaposi's sarcoma-related herpesvirus (KSHV) [11], Epstein-Barr virus (EBV) [44], herpes simplex virus 1 (HSV-1) [45] and human immunodeficiency virus (HIV-1) [46]. On the contrary, dsDNA sensing by IFI16 is length dependent [2], with dsDNA fragments of 150 base pairs reportedly being favourable for the formation of an optimal binding cluster of approximately ten IFI16 protomers [47].…”

“…The IFI16:STING association occurs in the cytosol following either cytosolic or nuclear DNA detection, as after herpesvirus DNA detection by nuclear IFI16 this portion of activated IFI16 translocates to the cytosol [11,49]. How exactly nuclear export of IFI16 is regulated after DNA sensing remains to be determined, but may involve .…”

“…However, abortive infection of CD4 + T cells with HIV, which leads to accumulation of HIV DNA, causes IFI16-dependent pyroptosis [51], since like AIM2, IFI16 activation can also promote inflammasome activation in some contexts. IFI16-dependent inflammasome activation has been reported to also occur after infection with herpes viruses such as KSHV, HSV-1 and EBV [11,44,45]. However, HSV-1 and HCMV infection can also result in IFI16 dependent IFN-b induction via the STING/TBK1 pathway.…”

“…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].…”

Les inflammasomes

“…L'extrémité amino-terminale contient un domaine PYD qui interagit avec le domaine PYD d'autres protéines (par exemple ASC [apoptosis-associated Speck-like protein]) afin de former des macrocomplexes ayant un rôle dans l'inflammation et la mort cellulaire. Seuls AIM2 et IFI16 ont été décrits comme inducteurs de l'inflammasome suite à la détection d'ADN dans le cytoplasme et dans le noyau, respectivement [10,11].…”