Abstract B196: Examining proteasome sensitivity of lymphoid malignancy: Ubiquilin 1 (Ubqln1) is required for BCR-induced proliferation of B cells

Abstract

Careful regulation of protein levels is essential to cellular life, and the ubiquitin proteasome system is a major way in which cells coordinate the degradation of proteins. In addition to regulating steady state protein degradation, the ubiquitin proteasome system assists in major proteome reorganizations, including the response to cellular stresses and the completion of major milestones such as differentiation, stimulation, and cell division. Lymphocytes are a useful model with which to understand the regulation of protein degradation because they undergo dramatic proteome reorganization upon receptor:ligand interactions, and because some lymphocytic malignancies are uniquely sensitive to treatment with proteasome inhibitors. We have previously shown that B lymphocytes require Ubiquilin 1 (Ubqln1), an extrinsic proteasome receptor, for their proliferation downstream of BCR stimulation. Ubqlns help to facilitate the degradation of ubiquitinated protein by simultaneously binding the cap of the proteasome and ubiquitinated client proteins, but until recently the clients of Ubqln1, as well as the consequences of Ubqln1 loss, were unknown. The lack of Ubqln1 resulted in accumulation of mislocalized mitochondrial proteins and induced a block in protein synthesis downstream of BCR stimulation, which resulted in cell cycle inhibition. This work implicated a role for Ubqln1 both in immune activation as well as B cell malignancy. Unexpectedly, TLR stimulation was normal in Ubqln1-deficienT-cells. Two major hypotheses for this specificity involve unique signal transduction pathway activation, and overexpression of mitochondrial proteins downstream of BCR activation. In fact, dysregulation of BCR signal transduction cascades and upregulation of OXPHOS genes define common and partially overlapping subtypes of diffuse large B-cell lymphoma (DLBCL). Currently, we aim to resolve these hypotheses with both in vivo and in vitro approaches. These studies will sharpen our understanding of B-cell cancer susceptibility to perturbation of the ubiquitin proteasome system and of Ubqln1 function. Citation Format: Alexandra M. Whiteley, Eric Brown, Daniel Finley. Examining proteasome sensitivity of lymphoid malignancy: Ubiquilin 1 (Ubqln1) is required for BCR-induced proliferation of B cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B196.