Biology subjects

Weinzettl, P.

Publications and source records attributed to Weinzettl, P..

3 recordsLinked to original sources

bioRxiv2026

Differential isoform-specific control of KCC2 function in developing cortical neurons

The K-Cl cotransporter KCC2 is essential for fast synaptic inhibition in the mature brain. It is encoded by a single gene and expressed as two isoforms: KCC2a and KCC2b, which differ in their N-terminal domains. While KCC2b is predominant, the function of the weakly expressed KCC2a isoform remains unclear. Here, we reveal that KCC2a is a potent, bidirectional regulator of KCC2b membrane stability and function in cortical neurons. In immature neurons, where WNK-SPAK kinase activity is high, KCC2a promotes SPAK-dependent phosphorylation of KCC2b at Thr1007, which likely contributes to hindering its membrane expression and function. Conversely, in mature neurons with low basal WNK-SPAK activity, KCC2a promotes KCC2b expression, clustering, and function. At this stage, although accounting for less than 5% of total KCC2 mRNA, KCC2a is enriched in dendrites and within KCC2 clusters, where it prevents clathrin-mediated KCC2b endocytosis, as well as polyubiquitination and proteasomal degradation. Thus, KCC2a acts as a developmental switch that first inhibits KCC2b during early development and then ensures its membrane stability to support effective synaptic inhibition in the adult brain.

neuroscience↗

bioRxiv2025

CD74 regulates antitumor immunity in melanoma by reprogramming dendritic cell immunogenicity and migration

Metastatic cutaneous melanoma remains a major therapeutic challenge, as many patients fail to respond or relapse following immune checkpoint therapy. The function of CD74, originally described as an MHC-II chaperone and receptor for macrophage migration inhibitory factor, remains poorly understood in tumor immunity. In this study, we show that systemic CD74 deletion in a syngeneic melanoma model significantly delayed tumor growth and reshaped the tumor immune microenvironment, and synergized with immune checkpoint blockade. Tumors in Cd74-/- mice had more effector and memory CD8+ T cells producing IFN-{gamma} and granzyme B than in control mice. Loss of CD74 promoted expansion of migratory cDC1s with elevated MHC-I and CCR7 expression. Cd74-/- professional antigen presenting cells increased cross-priming capacity for tumor-derived antigens in vivo and in vitro. Absence of CD74 induced the expression of CCR7, a key lymph node homing molecule, on cDCs and enhanced their ability to migrate towards the CCL19 ligand in single cell tracking analyses. These findings identify CD74 as a regulator of dendritic cell function and a promising therapeutic target to improve melanoma immunogenicity. One Sentence SummaryCD74 restrains cross-priming and migration capacity of dendritic cells, leading to impaired CD8+ T-cell infiltration and activation in tumor immunity.

immunology↗

bioRxiv2024

Stiffness-dependent LOX regulation via HIF-1 drives extracellular matrix modifications in psoriasis

Psoriasis is a common chronic inflammatory skin disease characterized by a thickened epidermis with elongated rete ridges and massive inflammatory immune cell infiltration. It is currently unclear what impact mechanoregulatory aspects in the dermis may have on disease progression. Using multiphoton second harmonic generation microscopy we found that the extracellular matrix (ECM) was profoundly reorganized within the dermis in psoriasis compared to healthy skin. Collagen fibers were highly aligned and assembled into thick, long collagen bundles, whereas the overall fiber density was reduced in psoriasis. This was particularly pronounced within dermal papillae extending into the epidermis. Further, the enzyme LOX, a crucial posttranslational modifier of ECM molecules, was highly upregulated in the dermis of psoriasis patients. In vitro functional and knock-down experiments identified a novel link between HIF-1 stabilization and LOX protein regulation in mechanosensitive skin fibroblasts. LOX secretion and activity directly correlated with substrate stiffness, and was independent of hypoxia and IL-17. Finally, scRNA-seq analysis identified skin fibroblasts expressing high amounts of LOX and other ECM-relevant genes and confirmed elevated HIF-1 expression in psoriasis. Our findings suggest a potential yet undescribed mechanical aspect of psoriasis stemming from disordered ECM architecture in the papillary dermis, which could initiate a positive feedback loop in fibroblasts driven by mechanical forces. This mechanism may contribute to tissue stiffening and diminished skin elasticity in psoriasis, potentially exacerbating its pathogenesis.

cell biology↗