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Prion ‐ like protein polymerisation underlies signal transduction in innate immunity: the emergence of a universal mechanism ?
Author(s) -
O'Carroll Ailis,
Ve Thomas,
Lau Derrick,
Giles Nichole,
Moustaqil Mehdi,
Bhumkar Akshay,
Hunter Dominic,
Kobe Bostjan,
Boecking Till,
Sierecki Emma,
Gambin Yann
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.814.3
Subject(s) - innate immune system , microbiology and biotechnology , biology , signal transducing adaptor protein , signal transduction , inflammasome , pattern recognition receptor , receptor , genetics
The innate immune system uses a multitude of receptors such as Toll‐like Receptors and Nod‐like Receptors to sense pathogens and danger signals. Upon their activation, a signalling cascade is initiated culminating in the transcription and translation of cytokines and other proteins vital for host protection. Recent studies have discovered that an array of these intracellular signalling proteins assemble into oligomeric signalling platforms, consequently amplifying the transmission of the signal from the stimulated receptor to the activation of relevant transcription machinery. Unexpectedly, it was also discovered that some of these proteins present in innate immune signalling such as the inflammasome adaptor protein ASC and the mitochondrial membrane‐associated protein MAVS, can form fibrils. These fibrils can elongate in a prion‐like manner to create super‐sized signalling platforms. In this study, we screened over 100 innate immune intracellular signalling proteins using single molecule fluorescence. We defined the oligomerisation and aggregation propensity of these proteins and track the specific signature of polymerisation. We identified multiple candidates forming super‐sized protein aggregates; through protein seeding experiments, we were able to conclude that ~20 of these proteins could self‐propagate aggregation as found in prion‐like mechanisms. These innate immune cytosolic proteins are not isolated to one signalling pathway but transverse most, if not all, signalling pathways of innate immune defence, inflammation and cell death. Intriguingly, some of these proteins could act to regulate and even inhibit the signalling cascade through their prion‐like protein propagation. Together these findings reveal a universal mechanism where the creation of polymer‐like platforms increases the number of binding sites and dramatically amplifies the signal. Our observations also suggest a complex interplay among the major signalling cascades of the innate immune system, in which prion‐like polymerization underlies the backbone of intracellular communication.