Biology subjects

Mobach, S.

Publications and source records attributed to Mobach, S..

3 recordsLinked to original sources

bioRxiv2024

Inhibition of constitutive activity of the atypical chemokine receptor ACKR3 by the small-molecule inverse agonist VUF16840

The atypical chemokine receptor 3 (ACKR3) has emerged as a promising drug target for the treatment of cancer, cardiovascular, and autoimmune diseases. In this study, we present the pharmacological characterization of VUF16840, the first small-molecule inverse agonist of ACKR3. VUF16840 effectively displaces CXCL12 binding to ACKR3 and inhibits chemokine-induced {beta}-arrestin2 recruitment in a concentration-dependent manner. Furthermore, VUF16840 stabilizes the inactive conformation of ACKR3, as demonstrated by its ability to suppress constitutive {beta}-arrestin2 recruitment. This inverse agonism alters ACKR3 constitutive trafficking, leading to receptor enrichment at the plasma membrane and inhibition of intracellular CXCL12 uptake. Importantly, VUF16840 exhibits high selectivity for ACKR3 over a broad panel of human chemokine receptors. These findings establish VUF16840 as a potent and selective ACKR3 inverse agonist capable of modulating constitutive and chemokine-induced signaling and internalization events. As such, VUF16840 represents a valuable pharmacological tool for exploring the molecular and translational roles of ACKR3 in both physiological and pathological contexts.

pharmacology and toxicology↗

bioRxiv2024

Disruption of basal CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

The chemokine receptor CXCR4 is overexpressed in many cancers and contributes to pathogenesis, disease progression, and resistance to therapies. CXCR4 is known to form oligomers, but the potential functional relevance in malignancies remain elusive. Using a newly established nanobody-based BRET method, we demonstrate that oligomerization of endogenous CXCR4 on lymphoid cancer cell lines correlates with enhanced expression levels. Specific disruption of CXCR4 oligomers reduced basal cell migration and pro-survival signaling via changes in the phosphoproteome, indicating the existence of basal CXCR4-oligomer-mediated signaling. Oligomer disruption also inhibited growth of primary CLL 3D spheroids and sensitized primary malignant cells to clinically used Bcl-2 inhibitor venetoclax. Given its limited efficacy in some patients and the ability to develop resistance, sensitizing malignant B-cells to venetoclax is of clinical relevance. Taken together, we established a new, non-canonical and critical role for CXCR4 oligomers in lymphoid neoplasms and demonstrated that selective targeting thereof has clinical potential. Significance statementClass A GPCRs, including the chemokine receptor CXCR4, can form oligomers, but their functional relevance remains poorly understood. This study provides evidence for the role of basal CXCR4 oligomers in lymphoid neoplasms, where they drive pro-survival signaling, migration, and tumor growth. We use a novel nanobody-based BRET method to demonstrate that endogenous CXCR4 constitutively oligomerizes in lymphoid cancer cells, correlating with receptor expression levels. Pharmacological disruption of these oligomers reduces tumor- associated signaling, impairs spheroid growth, and sensitizes patient-derived malignant cells to the apoptosis-inducing drug Venetoclax. Since CXCR4 is frequently overexpressed and potentially clustered in various malignancies, this work offers broader implications for enhancing treatment efficacy, overcoming drug resistance, and potentially reducing side effects across multiple cancer types.

biochemistry↗

bioRxiv2020

DNA polymerase β prevents AID-instigated mutagenic non-canonical mismatch DNA repair

In B cells, the error-prone repair of activation-induced cytidine deaminase (AID)-induced lesions in immunoglobulin variable genes cause somatic hypermutation (SHM) of antibody genes. Due to clonal selection in the germinal centers (GC) this active mutation process provides the molecular basis for antibody affinity maturation. AID deaminates cytosine (C) to create uracil (U) in DNA. Typically, the short patch base excision repair (spBER) effectively restores genomic U lesions. We here demonstrate that GC B cells actively degrade DNA polymerase {beta} (Pol{beta}), resulting in the inactivation of the gap-filling step of spBER. Consequently, lesions instigated by AID, and likely other base damages, are channeled towards mutagenic non-canonical mismatch repair (mncMMR), responsible for the vast majority of mutations at adenine and thymine (A:T) bases. Apparently, GC B cells prohibit faithful spBER, thereby favoring A:T mutagenesis during SHM. Lastly, our data suggest that the loss of Pol{beta} relates to hypoxia that characterizes the GC microenvironment.

immunology↗