Lymphoid-specific high-efficiency beta-catenin protein degradation

As part of canonical WNT signaling, beta-catenin forms activating transcriptional complexes with TCF7 factors to promote MYC-expression and proliferation in epithelial, neuronal, endothelial and mesenchymal cells. Despite its critical role in multiple organ systems, beta-catenin is dispensable for normal lymphopoiesis. While other cell types depend on beta-catenin to promote MYC-expression and proliferation, we discovered that B-lymphoid cells have evolved and critically depend on a previously unrecognized mechanism for high-efficiency beta-catenin protein degradation. beta-catenin mRNA levels in B-lymphoid cells were comparable to other cell types, however, beta- catenin protein levels were 80- to 200-fold lower and often undetectable. Lymphoid-specific high-efficiency beta-catenin protein degradation depends on concerted activity of the GSK3B and CK1a kinases, NEDD8-activating enzyme NAE1, and the immunoproteasome subunits PSMB8 and PSMB9. Inhibition or genetic haploinsufficiency of any of these components, reduced degradation efficiency, resulting in beta-catenin accumulation and acute cell death of B-lymphoid cells. In contrast to activating beta-catenin:TCF7 complexes that promote MYC-expression in other cell types, our studies in B-cells revealed repressive beta-catenin complexes with lymphoid Ikaros factors that induced transcriptional repression of MYC and acute cell death. We propose three Aims to (1) elucidate the mechanistic basis of high-efficiency beta-catenin protein degradation in B-lymphoid cells, (2) B-cell-specific composition and function of repressive beta-catenin complexes and (3) to develop concepts for therapeutic intervention at the level of GSK3B, CK1a, NAE1 and PSMB8 to disrupt beta- catenin protein degradation in B-cell autoimmune and lymphoproliferative conditions. Project Number: 1R01AI192914-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Markus Müschen | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $3,131,408 | Activity Code: R01 | Study Section: Molecular and Structural Immunology Study Section[MSI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19291401