Christianson Group | Target discovery and proteostasis mechanisms in disease

TARGETING ER HOMEOSTASIS IN MULTIPLE MYELOMA

The haematological malignancy multiple myeloma (MM) is typified by proliferation of clones producing excessive amounts of non-functional immunoglobulin, which interfere with normal haematopoietic functions in bone marrow. The plasma cells from which MM arises are highly optimised protein factories, assembling antibodies in the endoplasmic reticulum (ER) at rates nearing ~1x103/cell/sec. Robust, adaptive quality control (QC) machinery safeguard integrity of this secretory cargo by facilitating maturation while eliminating aberrant (and potentially toxic) forms that invariably arise. These tandem activities enable the ER to maintain homeostasis while accommodating elevated rates of protein flux.

With a hypersecretory phenotype, MM is a disease tacitly relying on the QC machinery maintaining ER homeostasis to remain viable. Strategies that disrupt ER homeostasis have proved therapeutically beneficial for MM. Proteasome inhibitors (e.g. bortezomib) that block protein degradation which elevates ER stress to levels sufficient enough to activate cell death pathways and abate proliferation, exemplify this strategy. However, patients eventually become resistant to these compounds, likely due to cellular adaptation through enhancement of alternative protein degradation pathways. Thus, identifying cellular targets and processes in MM linked with ER homeostasis, which are non-redundant and thus more difficult to bypass and/or adapt to for viability (i.e. an Achilles heel), remains an important endeavour to find new therapeutic opportunities.

Our laboratory is defining the extensive network of ER-resident ubiquitination machinery, their functions and relationship to organelle homeostasis. Of particular interest are ubiquitin-related candidates that sensitise proteasome inhibitor-resistant model cell lines, as they may reflect alternative points for apoptotic entry. ER homeostasismechanisms represent potentially valuable targets for therapeutic strategies to induce stress and cause cell death in MM. From our insight into the ubiquitination mechanisms at the ER, we are in search of those essential components whose disruption is able to induce ER stress and cell death and may represent new targets for therapeutic intervetion.