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Media type:
E-Article
Title:
TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF) forms filamentous structures, whose pro‐apoptotic signalling is terminated by autophagy
Contributor:
Gentle, Ian E.;
McHenry, Kevin T.;
Weber, Arnim;
Metz, Arlena;
Kretz, Oliver;
Porter, Dale;
Häcker, Georg
Description:
<jats:p>The formation of amyloid‐like protein structures has recently emerged as a feature in signal transduction, particularly in innate immunity. These structures appear to depend on defined domains for their formation but likely also require dedicated ways to terminate signalling. We, here, define the innate immunity protein/Toll‐like receptor adaptor TIR‐domain‐containing adapter‐inducing interferon‐β (<jats:styled-content style="fixed-case">TRIF</jats:styled-content>) as a novel platform of fibril formation and probe signal initiation through <jats:styled-content style="fixed-case">TRIF</jats:styled-content> as well as its termination in Toll‐like receptor 3 (<jats:styled-content style="fixed-case">TLR</jats:styled-content>3)‐stimulated melanoma cells. A main signalling pathway triggered by <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 caused apoptosis, which was controlled by inhibitor of apoptosis proteins and was dependent on <jats:styled-content style="fixed-case">RIPK</jats:styled-content>1 and independent of <jats:styled-content style="fixed-case">TNF</jats:styled-content>. Using correlative electron/fluorescence microscopy, we visualised fibrillar structures formed through both Toll/interleukin‐1 receptor and RIP homotypic interacting motif regions of <jats:styled-content style="fixed-case">TRIF</jats:styled-content>. We provide evidence that these fibrillary structures are active signalling platforms whose activity is terminated by autophagy. <jats:styled-content style="fixed-case">TRIF</jats:styled-content>‐signalling enhanced autophagy, and fibrillary structures were partly contained within autophagosomes. Inhibition of autophagy increased levels of pro‐apoptotic <jats:styled-content style="fixed-case">TRIF</jats:styled-content> complexes, leading to the accumulation of active caspase‐8 and enhanced apoptosis while stimulation of autophagy reduced <jats:styled-content style="fixed-case">TRIF</jats:styled-content>‐dependent death. We conclude that pro‐death signals through <jats:styled-content style="fixed-case">TRIF</jats:styled-content> are regulated by autophagy and propose that pro‐apoptotic signalling through <jats:styled-content style="fixed-case">TRIF</jats:styled-content>/<jats:styled-content style="fixed-case">RIPK</jats:styled-content>1/caspase‐8 occurs in fibrillary platforms.</jats:p>