TIR-domain-containing adapter-inducing interferon-β (TRIF) forms filamentous structures, whose pro-apoptotic signalling is terminated by autophagy
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TIR-domain-containing adapter-inducing interferon-β (TRIF) forms filamentous structures, whose pro-apoptotic signalling is terminated by autophagy. / Gentle, Ian E; McHenry, Kevin T; Weber, Arnim; Metz, Arlena; Kretz, Oliver; Porter, Dale; Häcker, Georg.
in: FEBS J, Jahrgang 284, Nr. 13, 07.2017, S. 1987-2003.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - TIR-domain-containing adapter-inducing interferon-β (TRIF) forms filamentous structures, whose pro-apoptotic signalling is terminated by autophagy
AU - Gentle, Ian E
AU - McHenry, Kevin T
AU - Weber, Arnim
AU - Metz, Arlena
AU - Kretz, Oliver
AU - Porter, Dale
AU - Häcker, Georg
N1 - © 2017 Federation of European Biochemical Societies.
PY - 2017/7
Y1 - 2017/7
N2 - 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 (TRIF) as a novel platform of fibril formation and probe signal initiation through TRIF as well as its termination in Toll-like receptor 3 (TLR3)-stimulated melanoma cells. A main signalling pathway triggered by TLR3 caused apoptosis, which was controlled by inhibitor of apoptosis proteins and was dependent on RIPK1 and independent of TNF. Using correlative electron/fluorescence microscopy, we visualised fibrillar structures formed through both Toll/interleukin-1 receptor and RIP homotypic interacting motif regions of TRIF. We provide evidence that these fibrillary structures are active signalling platforms whose activity is terminated by autophagy. TRIF-signalling enhanced autophagy, and fibrillary structures were partly contained within autophagosomes. Inhibition of autophagy increased levels of pro-apoptotic TRIF complexes, leading to the accumulation of active caspase-8 and enhanced apoptosis while stimulation of autophagy reduced TRIF-dependent death. We conclude that pro-death signals through TRIF are regulated by autophagy and propose that pro-apoptotic signalling through TRIF/RIPK1/caspase-8 occurs in fibrillary platforms.
AB - 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 (TRIF) as a novel platform of fibril formation and probe signal initiation through TRIF as well as its termination in Toll-like receptor 3 (TLR3)-stimulated melanoma cells. A main signalling pathway triggered by TLR3 caused apoptosis, which was controlled by inhibitor of apoptosis proteins and was dependent on RIPK1 and independent of TNF. Using correlative electron/fluorescence microscopy, we visualised fibrillar structures formed through both Toll/interleukin-1 receptor and RIP homotypic interacting motif regions of TRIF. We provide evidence that these fibrillary structures are active signalling platforms whose activity is terminated by autophagy. TRIF-signalling enhanced autophagy, and fibrillary structures were partly contained within autophagosomes. Inhibition of autophagy increased levels of pro-apoptotic TRIF complexes, leading to the accumulation of active caspase-8 and enhanced apoptosis while stimulation of autophagy reduced TRIF-dependent death. We conclude that pro-death signals through TRIF are regulated by autophagy and propose that pro-apoptotic signalling through TRIF/RIPK1/caspase-8 occurs in fibrillary platforms.
KW - Adaptor Proteins, Vesicular Transport
KW - Animals
KW - Apoptosis
KW - Autophagy
KW - Blotting, Western
KW - Caspase 8
KW - Cell Line, Tumor
KW - Cells, Cultured
KW - HEK293 Cells
KW - HeLa Cells
KW - Humans
KW - Mice, Knockout
KW - Microscopy, Electron, Transmission
KW - Microscopy, Fluorescence
KW - Oligopeptides
KW - Poly I-C
KW - Receptor-Interacting Protein Serine-Threonine Kinases
KW - Signal Transduction
KW - Toll-Like Receptor 3
KW - Journal Article
U2 - 10.1111/febs.14091
DO - 10.1111/febs.14091
M3 - SCORING: Journal article
C2 - 28453927
VL - 284
SP - 1987
EP - 2003
JO - FEBS J
JF - FEBS J
SN - 1742-464X
IS - 13
ER -