1. Differential Interactome and Innate Immune Response Activation of Two Structurally Distinct Misfolded Protein Oligomers
- Author
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Cintia Roodveldt, Giulia Fani, Kathryn S. Lilley, Benedetta Mannini, David Pozo, Fabrizio Chiti, Jaime M. Franco, Christopher M. Dobson, Giulia Vecchi, Adahir Labrador-Garrido, Bertrand Fabre, Michele Vendruscolo, Agencia Estatal de Investigación (España), Federation of European Biochemical Societies, EMBO, Società Italiana di Biochimica e Biologia Molecolare, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Universidad de Sevilla, and University of Cambridge
- Subjects
Cell signaling ,Physiology ,Cognitive Neuroscience ,Plasma protein binding ,Neurodegenerative disease ,Biochemistry ,Interactome ,Protein Aggregation, Pathological ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Neuroinflammation ,Cricetinae ,medicine ,Animals ,Humans ,030304 developmental biology ,Innate immunity ,0303 health sciences ,Innate immune system ,Chemistry ,Escherichia coli Proteins ,Neurodegeneration ,Cell Biology ,General Medicine ,Molecular mechanisms ,medicine.disease ,Immunity, Innate ,Cell biology ,Misfolded oligomers ,Carboxyl and Carbamoyl Transferases ,Protein folding ,Microglia ,030217 neurology & neurosurgery ,Protein Binding ,Protein misfolding - Abstract
The formation of misfolded protein oligomers during early stages of amyloid aggregation and the activation of neuroinflammatory responses are two key events associated with neurodegenerative diseases. Although it has been established that misfolded oligomers are involved in the neuroinflammatory process, the links between their structural features and their functional effects on the immune response remain unknown. To explore such links, we took advantage of two structurally distinct soluble oligomers (type A and B) of protein HypF-N and compared the elicited microglial inflammatory responses. By using confocal microscopy, protein pull-down, and high-throughput mass spectrometry, we found that, even though both types bound to a common pool of microglial proteins, type B oligomers - with a lower solvent-exposed hydrophobicity - showed enhanced protein binding, correlating with the observed inflammatory response. Furthermore, the interactome associated with inflammatory-mediated neurodegeneration revealed previously unidentified receptors and signaling molecules likely to be involved in the oligomer-elicited innate immune response., Financial support was provided by FEBS (Short-Term Fellowship to B.M.), EMBO (ASTF 450-2013 to B.M.), the Italian Society of Biochemistry and Molecular Biology (B.M.), the Spanish Ministry of Economy (RTC-2015-3309-1 to C.R., ISCIII CPII16/58 to C.R., PI14-1600 to D.P., and RTI2018- 098432-B-I00 to C.R. and D.P.), the Regional Ministry of Economy (P11-CTS-8161 and PAIDI2020 CTS-677 to D.P.), Programa “Atraccion de Talento ́ ”, University of Seville, and Programa “Ramon y Cajal ́ ”, Spanish Ministry of Economy (RYC-2017-23127 to C.R.). This work was also supported by the Cambridge Centre for Misfolding Diseases (B.M., G.V., G.F., M.V., C.M.D.).
- Published
- 2019