Proteasome Targeting for Alloreactive Plasma Cells

Abstract The induction of plasma cells that secrete antibodies against donor tissue alloantigens is a major barrier to successful transplantation. Moreover, because many plasma cells are remarkably long-lived, the resulting antibody titers are exceptionally durable. Hence strategies are needed to eliminate long-lived plasma cells that generate allospecific antibodies. A current dominant strategy for depleting plasma cells centers on compounds that interfere with the proteasome. Plasma cells are thought to uniquely require proteasome function to survive. However, for reasons unclear, substantial numbers of allospecific plasma cells resist the action of available proteasome inhibitors (PIs). This project centers on the central hypothesis that mature long-lived plasma cells (LLPCs) are especially resistant to PI-induced cell death. Our experiments test this idea while also working towards defining how the proteasome interfaces with regulators within the endoplasmic reticulum such as the chaperone protein BiP and other cytosolic regulators of proteostasis including the autophagy regulator p62 and VCP/p97, an ATPase that controls movement of proteins from the ER into the cytosol. Specifically, we will: 1) Define the role of BiP in controlling PI sensitivity in LLPCs, 2) Define the key regulators of ER-to-cytosol protein trafficking/disposal and their role in controlling PI sensitivity in LLPCs, and 3) Identify the gene regulatory networks underlying LLPC resistance to PIs. .