Title : "A new role for NAP1/AZI2 in the regulation of the interferon (IFN) induction pathway through the formation of TBK1-trapping condensate"

TANK-binding kinase 1 (TBK1) is a central regulator of type I IFN production. It is located at the crossroads of several signaling pathways, including those triggered by TLR3, RLRs, and cGAS. TBK1-adaptor proteins (NAP1/AZI2, SINTBAD/TBKBP1 and TANK) compete with each other in binding to the kinase. Several experiments have shown that they are positive regulators of the IFN induction pathway. However, recent observations have challenged this view.   

We demonstrate that upon activation of the MAVS- or the cGAS-STING-dependent IFN induction pathway, NAP1, SINTBAD and TANK formed condensates with characteristics of transient organelles formed by liquid-liquid phase separation. We show that NAP1 condensates are able to sequester TBK1 while the kinase has a negative impact on the formation of condensates formed by TANK and SINTBAD.

Importantly, in HEK293T or in NAP1^KO HAP1 KO cell lines, we observed an increase in IFN‑b mRNAs compared to parental cell lines when exposed to several distinct stimuli. We discovered that NAP1 actually has a dual effect on the kinase activity. First, by binding to TBK1, NAP1 increases its activity and therefore leads to enhanced activation of the IFN pathway. Then, NAP1 phosphorylation by TBK1 lowers the critical concentration of NAP1, favoring the formation of condensates in which TBK1 and the PP2A phosphatase complex concentrate. Within these condensates, the PP2A complex dephosphorylates TBK1, resulting in a limitation of the IFN activation pathway.

Finally, we show that NAP1 variants found in patients with lupus or interferonopathies are unable to form condensates upon exposure of cells to danger signals and are therefore only able to activate TBK1 but not to limit its activity.

This work highlights a novel and original way to regulate a signal pathway by the formation of liquid condensates and provides a molecular explanation for certain interferonopathies."

Contact : nadine.laguette@igmm.cnrs.fr

Researchers from BIOLuM come down with any poster to discuss about their science (together, & with any colleague from the "pôle Balard" or the "CEFE" interested to know about their neighbour's research).

https://meetings.embo.org/event/25-climate-resilience

https://meetings.embo.org/event/25-climate-resilience

Interaction of Perilipin 4 with lipid droplets

https://meetings.embo.org/event/25-climate-resilience

https://meetings.embo.org/event/25-climate-resilience

https://www.linkedin.com/in/ingrid-masse-8b373517/