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Understanding the Functional Consequences of Ubiquitin Depletion During B- to Plasma Cell Differentiation

We previously demonstrated that in physiologic B-cell to plasma cell differentiation, proteasome activity is reduced, and protein synthesis is significantly increased, resulting in accumulation of lysine-48 (K48)-polyubiquitinated proteins, preceding massive plasma cell apoptosis. The underlying cause of plasma cell apoptosis after antigen encounter is unknown, but a yet unidentified counter or timer for live/death fate has been previously proposed. We hypothesize that sequestration of ubiquitin in K48-polyubiquitinated protein aggregates would lead to depletion of the free ubiquitin pool. We postulated that free ubiquitin depletion is the main determinant of plasma cell apoptosis, and we are using advanced, quantitative proteomic tools to investigate this hypothesis.

Targeting Proteostasis as a Novel Therapeutic Strategy in AL Amyloidosis

Intact immunoglobulins (Ig) and free light chains (FLC) are abundantly secreted by clonal plasma cells. AL amyloidosis (AL) is a plasma cell (PC) disorder whose pathogenesis is invariably related to deposition of Ig FLC fibrils in target organs, such as heart and kidneys, leading to progressive organ failure. Although treatable, AL is incurable and only one therapy is FDA approved, representing an urgent, unmet clinical need. The molecular mechanisms underlying FLC synthesis/secretion remain obscure and therapeutic strategies directly targeting it do not exist. We and others have previously shown that normal and clonal PC suffer from baseline proteotoxicity due to a mismatch between intensive and inaccurate protein synthesis and insufficient proteasome-mediated protein degradation. This intrinsic vulnerability makes PC selectively sensitive to agents perturbing the protein homeostasis (proteostasis) network, such as proteasome inhibitors. By using botulinum neurotoxin as a research tool, we provide proof of concept that targeting FLC secretion is feasible and of potential therapeutic utility in AL. We are interested in identifying the proteins that govern FLC secretion to develop novel, effective therapies for AL.

Targeting Proteasome Stress Response as a Novel Therapeutic Strategy in MM

We previously showed that augmenting proteasome activity leads to therapeutic resistance to proteasome inhibitors in multiple myeloma. Eukaryotic cells rely on the NRF1 transcription factor to induce de novo proteasome biogenesis when proteasome activity is insufficient to maintain proteolytic demand, a phenomenon called proteasome stress response. Our preliminary data show that genetic disruption of NRF1 is detrimental for MM cell growth in baseline conditions and upon proteasome inhibitor treatment. Similarly, targeting DDI2, an aspartate protease responsible for proteolytic cleavage of NRF1, leads to loss of NRF1 activation, resulting in increased sensitivity of MM cells to proteasome inhibitors and blunting of proteasome stress response. As part of this project, we are developing a proteasome stress reporter to aid in repurposing screening of compounds that may target this pathway and have clinical utility in plasma cell disorders.

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