👤 Janina Petry

Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects. We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants. Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns. Different adjuvants induce distinct IgG This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC. Show less

Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype and are regulated through diverse signaling networks involving kinases and transcription factors. This study establishes an estrogen receptor (ERα)/MAPK (ERK5)/cofilin (CFL1) network that specifies the degree of breast cancer cell aggressiveness through coupling of actin reorganization and hormone receptor-mediated transcription. Using dominant negative and constitutively active forms, as well as small-molecule inhibitors of extracellular signal-regulated kinase (ERK)5 and MAP-ERK kinase (MEK)5, it was revealed that hormone activation of ERα determined the subcellular localization of ERK5, which functions as a coregulator of ERα-dependent gene transcription. Notably, ERK5 acted in concert with the actin remodeling protein, CFL1, and upon hormone exposure, both localized to active nuclear transcriptional hubs as verified by immunofluorescence and proximity ligation assays. Both ERK5 and CFL1 facilitated PAF1 recruitment to the RNA Pol II complex and both were required for regulation of gene transcription. In contrast, in cells lacking ERα, ERK5 and CFL1 localized to cytoplasmic membrane regions of high actin remodeling, promoting cell motility and invasion, thereby revealing a mechanism likely contributing to the generally poorer prognosis of patients with ERα-negative breast cancer. Thus, this study uncovers the dynamic interplay of nuclear receptor-mediated transcription and actin reorganization in phenotypes of breast cancer aggressiveness. Identification of the ER/ERK5/CFL1 axis suggests new prognostic biomarkers and novel therapeutic avenues to moderate cancer aggressiveness. Show less