Biology subjects

Balla, A.

Publications and source records attributed to Balla, A..

6 recordsLinked to original sources

bioRxiv2025

Adenylyl cyclase 9: fundamental change of regulation in vertebrates and gene sub-functionalization after teleost-specific whole-genome duplication

Adenosine 3:5 monophosphate (cAMP) is a ubiquitous signalling molecule generated by the adenylyl cyclase family of proteins which is encoded by ten genes. The biological significance of this diversity is not well understood. In mammals, transmembrane adenylyl cyclase 9 (AC9) is resistant to regulation by heterotrimeric G proteins. A major facet of this resistance is auto-inhibition -- in the presence of activated Gs, AC9 is inhibited by its C-terminal domain. Here, we examined the natural evolution of this seemingly paradoxical control mechanism. At the primary sequence level, the hallmarks of auto-inhibition are apparent in all vertebrates, none are found in invertebrates. Teleost-specific genome duplication (TGD) resulted in adcy9 ohnologs, one of which lacked the hallmarks of auto-inhibition. This was confirmed in functional assays upon cloning and heterologous expression of the requisite cDNAs. The tissue distributions of the adcy9 ohnologs in teleost species also pointed to their sub-functionalization. Above all, auto-inhibited adcy9 was largely restricted to the brain indicating a fundamental role in brain development or function. Our findings document a quantum leap of the regulation of the enzymatic activity of AC9 in vertebrates and the potency of TGD to meet an adaptational challenge through functionally diversified ohnologs.

evolutionary biology↗

bioRxiv2025

Loss of ESE3/EHF is sufficient to promote cell plasticity, transformation and androgen-independent status in the early stage of prostate carcinogenesis.

Phenotypic plasticity enables tumor progression and treatment resistance. However, its timing and underlying mechanisms are poorly understood. Here, we demonstrate that cell plasticity can emerge early during prostate cancer development, resulting from the knockout of the epithelial-specific ETS transcription factor EHF in prostate epithelial cells. Inspecting the transcriptome of human prostate cancers, we identified a correlation between low EHF expression, loss of luminal epithelial identity, and attenuated androgen signaling in both primary tumors and castration-resistant prostate cancers (CRPC). In EHF knockout mouse models and human epithelial cells, EHF ablation was sufficient to disrupt epithelial cell lineage integrity and promote a progenitor/stem cell-like state with both basal and luminal features, enabling high plasticity and multi-lineage phenotypic transitions. Mechanistically, EHF acted as a central node controlling a hierarchy of transcriptional regulatory factors and downstream signaling pathways (e.g., COL1A1/DDR1, JAK/STAT3), thereby regulating epithelial lineage integrity and restricting stemness and phenotypic transitions. Activation of these downstream pathways, consequent to EHF loss, promoted non-luminal cell features, attenuated androgenic response, and resistance to AR antagonists. Collectively, these data provide novel insights into the causes of phenotypic plasticity and androgen indifference already at the early stages of prostate tumorigenesis and a new perspective on the paths to cancer progression directly relevant to the development of more efficient treatment strategies.

cancer biology↗

bioRxiv2024

Natural variations of adult neurogenesis and anxiety predict hierarchical status of inbred mice

Hierarchy provides a survival advantage to social animals in challenging circumstances. In mice, social dominance is associated with trait anxiety and reduced stress resilience which are regulated by adult hippocampal neurogenesis. Here, we tested whether adult hippocampal neurogenesis may regulate social dominance behavior. We observed that future dominant individuals exhibited higher trait anxiety and lower levels of hippocampal neurogenesis prior to social hierarchy formation, suggesting that baseline neurogenesis might predict individual social status among a group. This phenotype persisted after social hierarchy was stable. Experimentally reducing neurogenesis prior to the stabilization of social hierarchy in group-housed males increased the probability of mice to become dominant and increased anxiety. Finally, when innate dominance was assessed in socially isolated and anxiety-matched animals, mice with impaired neurogenesis displayed a dominant status toward strangers. Together, these results indicate that adult neurogenesis predicts and regulates hierarchical and situational dominance behavior along with anxiety-related behavior. These results provide a framework to study the mechanisms underlying social hierarchy and the dysregulation of dominance behavior in psychiatric diseases related to anxiety.

neuroscience↗

bioRxiv2023

ArreSTick Motif is Responsible for GPCR-beta-Arrestin Binding Stability and Extends Phosphorylation-Dependent beta-arrestin Interactions to Non-Receptor Proteins

The binding and function of {beta}-arrestins are regulated by specific phosphorylation motifs present in G protein-coupled receptors (GPCRs). However, the exact arrangement of phosphorylated amino acids responsible for establishing a stable interaction remains unclear. To investigate this pattern, we employed a 1D sequence convolution model trained on a dataset of GPCRs that have established {beta}-arrestin binding properties. This approach allowed us to identify the amino acid pattern required for GPCRs to form stable interactions with {beta}-arrestins. This motif was named "arreSTick." Our data show that the model predicts the strength of the coupling between GPCRs and {beta}-arrestins with high accuracy, as well as the specific location of the interaction within the receptor sequence. Furthermore, we show that the arreSTick pattern is not limited to GPCRs, and is also present in numerous non-receptor proteins. Using a proximity biotinylation assay and mass spectrometry analysis, we demonstrate that the arreSTick motif controls the interaction between numerous non-receptor proteins and {beta}-arrestins. For example, the HIV-1 Tat Specific Factor 1 (HTSF1 or HTATSF1), a nuclear transcription factor, contains the arreSTick pattern, and our data show that its subcellular localization is influenced by its coupling to {beta}-arrestin2. Our findings unveil a broader regulatory role for {beta}-arrestins in phosphorylation-dependent interactions, extending beyond GPCRs to encompass non-receptor proteins as well.

biochemistry↗

bioRxiv2023

Receptor endocytosis orchestrates the spatiotemporal bias of β-arrestin signaling

The varying efficacy of biased and balanced agonists is generally explained by the stabilization of different active receptor conformations. In this study, systematic profiling of transducer activation of AT1 angiotensin receptor agonists revealed that the extent and kinetics of {beta}-arrestin binding exhibit substantial ligand-dependent differences, which however completely disappear upon the inhibition of receptor internalization. Even weak partial agonists for the {beta}- arrestin pathway acted as full or near full agonists, if receptor endocytosis was prevented, indicating that receptor conformation is not an exclusive determinant of {beta}-arrestin recruitment. The ligand-dependent variance in {beta}-arrestin translocation at endosomes was much larger than it was at the plasma membrane, showing that ligand efficacy in the {beta}-arrestin pathway is spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shape the effects of agonists on endosomal receptor-{beta}-arrestin binding and thus determine the extent of bias. Among others, ligand dissociation rate and G protein activity have particularly strong impact on receptor-{beta}-arrestin interaction, and their effects are integrated at endosomes. Our results highlight that endocytosis forms a key spatiotemporal platform for biased GPCR signaling and can aid the development of more efficacious functionally-selective compounds. One Sentence summaryAgonist-specific differences in {beta}-arrestin recruitment are mainly determined by the ligand dissociation rate and G protein activation at the endosomes.

cell biology↗

bioRxiv2020

Translational neurophysiological biomarkers of N-methyl-D-aspartate receptor dysfunction in serine racemase knockout mice

Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. Both PCP and SRKO led to significant increases of ASSR, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.

neuroscience↗