Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains - Institut Pasteur Accéder directement au contenu
Article Dans Une Revue (Data Paper) BMC Biology Année : 2023

Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains

Résumé

Background In a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic. It is generally thought that the cause for this differential solubility behaviour is solely found within the IgLC amino acid sequences, and a variety of individual sequence-related biophysical properties (e.g. thermal stability, dimerisation) have been proposed in different studies as major determinants of the aggregation in vivo. Here, we investigate biophysical properties underlying IgLC amyloidogenicity. Results We introduce a novel and systematic workflow, Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip), for detailed biophysical characterisation, and apply it to nine different MM patient-derived IgLCs. Our set of pathogenic IgLCs spans the entire range of values in those parameters previously proposed to define in vivo amyloidogenicity; however, none actually forms amyloid in patients. Even more surprisingly, we were able to show that all our IgLCs are able to form amyloid fibrils readily in vitro under the influence of proteolytic cleavage by co-purified cathepsins. Conclusions We show that (I) in vivo aggregation behaviour is unlikely to be mechanistically linked to any single biophysical or biochemical parameter and (II) amyloidogenic potential is widespread in IgLC sequences and is not confined to those sequences that form amyloid fibrils in patients. Our findings suggest that protein sequence, environmental conditions and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.
Fichier principal
Vignette du fichier
12915_2022_Article_1506.pdf (8.11 Mo) Télécharger le fichier
12915_2022_1506_MOESM1_ESM.pdf (1.51 Mo) Télécharger le fichier
12915_2022_1506_MOESM2_ESM.pdf (4.34 Mo) Télécharger le fichier
12915_2022_1506_MOESM3_ESM.pdf (3.51 Mo) Télécharger le fichier
12915_2022_1506_MOESM4_ESM.pdf (1.57 Mo) Télécharger le fichier
12915_2022_1506_MOESM5_ESM.pdf (2.72 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Licence : CC BY - Paternité
Licence : CC BY - Paternité
Licence : CC BY - Paternité
Licence : CC BY - Paternité
Licence : CC BY - Paternité
Licence : CC BY - Paternité

Dates et versions

pasteur-04099048 , version 1 (16-05-2023)

Licence

Paternité

Identifiants

Citer

Rebecca Sternke-Hoffmann, Thomas Pauly, Rasmus K Norrild, Jan Hansen, Florian Tucholski, et al.. Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains. BMC Biology, 2023, 21 (1), pp.21. ⟨10.1186/s12915-022-01506-w⟩. ⟨pasteur-04099048⟩
42 Consultations
75 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More