Research highlights

In this issue of The FEBS Journal, we highlight a study by Madine et al. that explores a potential treatment strategy for light-chain amyloidosis, and a report by Shortt and colleagues investigating how immunomodulatory imide drugs can impact the cereblon interactome. We also feature work by Polikarpov and co-authors exploring how the enzyme BlEst2 could be the founding member of a previously unrecognised subgroup of carboxylesterases. Image created using Wordclouds.com. Light-chain amyloidosis is a rare disease caused by the excessive production of free antibody light chains (LCs). These surplus non-functional LCs aggregate into fibrils that accumulate in multiple organs within the body, causing damage. Due to the systemic and non-specific nature of the symptoms, patients usually receive an amyloidosis diagnosis at a late stage, which is associated with poor prognosis and lower survival rates. There is no cure for this disease and while some therapeutic agents aimed at clearing amyloid deposits are currently under investigation, these are not commercially available. As an alternative to removing already formed amyloid fibrils, preventing their formation could be a feasible therapeutic approach. Therefore, developing strategies to maintain mono- or dimeric LCs in solution to prevent the formation of toxic amyloid deposits is a high-priority challenge. In this exciting study, Alana Maerivoet and co-authors used a phage-display screening approach and identified a variable heavy (VH) domain antibody fragment called ‘VH1’ that could bind to and stabilise LC monomers. They found that VH1 was able to inhibit fibril formation of an amyloidogenic LC called SMA, even when the concentration of SMA exceeded that of VH110-fold. The authors conclude that VH1 has therapeutic potential for the treatment of light-chain amyloidosis. Although optimistic, they recognise that further research should also focus on full-length amyloidogenic LCs, beyond SMA, as these have additionally been found in light-chain amyloidosis patients. Although immunomodulatory imide drugs (IMiDs) such as lenalidomide form the backbone of treatment strategies for multiple myeloma, resistance and toxicity frequently restrict their use. Mapping out how IMiD treatment affects cell signalling at a molecular level is therefore paramount to overcome this. Although IMiD toxicity has previously been linked to cereblon (CRBN), the underlying biological effects of these drugs remain incompletely understood. In their proof-of-concept study, Matteo Costacurta and colleagues developed a proximity biotinylation labelling assay using a BioID2 ligase-CRBN fusion protein to explore how the CRBN interactome is impacted by IMiDs. They identified nonmuscle myosin heavy chain IIA (MYH9) as a previously undescribed CRBN interactor and found that IMiD treatment further potentiated this interaction. In addition, they observed that the CRBN interactome significantly changes when the proteasome is inhibited. Given MYH9's role as a cytoskeletal protein, the authors speculate that this CRBN-MYH9 interaction could play an important role in platelet biology and function, thereby contributing to clinical phenotypes and haematological toxicities and thus highlighting the importance and translational potential of this strategy. Although the biochemical interaction between CRBN and MYH9 was substantiated, the functional consequences require validation and further assessment. The authors also conclude that this labelling technology could be applied to other E3-ligase and proteasome-modulating therapies to explore their effect on cell signalling and interaction networks. This study has great implications for the improvement of cancer treatment and patient quality of life. Understanding the biology behind drug toxicity and resistance can help navigate the side effects of standard cancer treatment, as well as inform the design and development of new and improved therapeutic agents. Carboxylesterases are ubiquitously present in nature and can metabolise a range of carboxyl esters, from those present in fatty acids to environmental pollutants and pharmaceuticals. The broad substrate spectrum of these enzymes makes them highly important for industrial use as biocatalysts. In this study, Nakamura, Godoy and co-authors characterised a previously undescribed carboxylesterase isolated from Bacillus licheniformis, BlEst2. Solving the crystal structure of this enzyme revealed an α/β-hydrolase fold core domain and an additional propeptide C-terminal domain. Intriguingly, the presence of a C-terminal propeptide domain is a feature attributed to some lipases, rather than esterases. In lipases, these propeptide C-terminal regions are associated with protein localisation and maintenance of quaternary structure. Here, cleaving the C-terminal domains of BlEst2 revealed its active structure and caused a marked increase in its enzymatic activity, indicating a regulatory role for this region. The authors speculate that in addition to acting as an intramolecular inhibitor of BlEst2, the C-terminal domain may play a role in protein folding and preventing cell membrane damage during transport. Their findings demonstrate that despite being structurally similar to lipases, BlEst2 is indeed an esterase. However, this structural similarity of BlEst2 to lipases suggests that it could be the first characterised member of a new and previously unrecognised subgroup of enzymes within the carboxylesterase family. This study highlights the limits imposed by the conventional enzyme classification system, which is based on sequence alignment and phylogenetics, and suggests that incorporating structural studies into this workflow might reveal new subgroups that don't conform to current classification paradigms. HK is employed by FEBS and is an Editor at The FEBS Journal.