Signal Transduction by a Fungal NOD-Like Receptor Based on Propagation of a Prion Amyloid Fold

In the fungus podospora anserina,the [het-s] prion induces programmed cell death by activating the het-s pore-forming protein. the het-s β-solenoid prion fold serves as a template for converting the het-s prion-forming domain into the same fold. this conversion,in turn,activates the het-s pore-forming domain. the gene immediately adjacent to het-s encodes nwd2,a nod-like receptor (nlr) with an n-terminal motif similar to the elementary repeat unit of the β-solenoid fold. nlrs are immune receptors controlling cell death and host defense processes in animals,plants and fungi. we have proposed that,analogously to [het-s],nwd2 can activate the het-s pore-forming protein by converting its prion-forming region into the β-solenoid fold. here,we analyze the ability of nwd2 to induce formation of the β-solenoid prion fold. we show that artificial nwd2 variants induce formation of the [het-s] prion,specifically in presence of their cognate ligands. the n-terminal motif is responsible for this prion induction,and mutations predicted to affect the β-solenoid fold abolish templating activity. in vitro,the n-terminal motif assembles into infectious prion amyloids that display a structure resembling the β-solenoid fold. in vivo,the assembled form of the nwd2 n-terminal region activates the het-s pore-forming protein. this study documenting the role of the β-solenoid fold in fungal nlr function further highlights the general importance of amyloid and prion-like signaling in immunity-related cell fate pathways. © 2015 daskalov et al.