Antibody-secreting cell differentiation and fitness is dependent on sialophorin CD43-mediated regulation of the unfolded protein response 3498

Abstract Description We identified sialophorin CD43 as a regulator of BCR signaling thresholds. Here, we investigated the role of CD43 in T-cell mediated antibody-secreting cell (ASC) differentiation. CD43 Ab-targeting thwarted BCR signals and proliferation, induced cell death and inhibited ASC-differentiation. CRISPR/Cas9 knockdown of CD43 in this primary B cell system confirmed ASC inhibition emphasizing the role of CD43 in B-cell effector differentiation. CD43-targeting on differentiated ASCs induced rapid apoptosis preceded by diminished Ab-production and XBP1s expression, indicating involvement of the unfolded protein response (UPR). Short-term CD43 targeting revealed Akt1-dependent transcriptional inhibibition of BLIMP1, a known regulator of the UPR in ASCs. CD43 targeting did not affect IRF4 expression, a canonical BLIMP1 transcription factor. We therefore searched for IRF4 post-translational modifications and found that BLIMP1 transcriptional regulation depended on histone deacetylase 11, known to enhance IRF4 binding to the PRDM1 (BLIMP1) promoter. This suggests that CD43-mediated BLIMP1 transcriptional regulation could rely on curbed IRF4 deacetylation reducing its binding to the PRDM1 promoter, modulating BLIMP1 and XBP1s expression and the UPR. We introduce a novel CD43-regulated pathway essential for ASC-differentiation and fitness that can be utilized therapeutically. Funding Sources Supported by South-Eastern Norway Regional Health Authority (Helse Sør-Øst) project number 2021066 and 2023022. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)