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6 recordsLinked to original sources
PubMed2026

Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.

Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP3 receptor Ca2+ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca2+ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca2+ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca2+ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy of ER-mitochondrial Ca2+ transfer without changing ER Ca2+ release, despite attenuating mitochondrial Ca2+ uptake. We find interaction between Bcl-xL and each IP3R isoform occurring at the mitochondria and a complex formed by OMM-localized Bcl-xL and IP3Rs. OMM Bcl-xL interacts with IP3Rs in trans at ER-mitochondrial contacts to optimize local Ca2+ signal propagation into the mitochondria.

Bcl-xL↗
PubMed2024

Contribution of A1 to macrophage survival in cooperation with MCL-1 and BCL-XL in a murine cell model of myeloid differentiation.

Myeloid cells are the first line of defence against pathogens. Mitochondrial apoptosis signalling is a crucial regulator of myeloid cell lifespan and modulates the function of myeloid cells. The anti-apoptotic protein BCL-2-family protein BCL2A1/A1/BFL-1 is strongly upregulated in inflammation in macrophages. We analysed the contribution of A1 to apoptosis regulation in a conditional system of in vitro differentiation of murine macrophages from immortalised progenitors. We disabled the expression of A1 by targeting all murine A1 isoforms in the genome. Specific inhibitors were used to inactivate other anti-apoptotic proteins. Macrophage progenitor survival mainly depended on the anti-apoptotic proteins MCL-1, BCL-XL and A1 but not BCL-2. Deletion of A1 on its own had little effect on progenitor cell survival but was sensitised to cell death induction when BCL-XL or MCL-1 was neutralised. In progenitors, A1 was required for survival in the presence of the inflammatory stimulus LPS. Differentiated macrophages were resistant to inhibition of single anti-apoptotic proteins, but A1 was required to protect macrophages against inhibition of either BCL-XL or MCL-1; BCL-2 only had a minor role in these cells. Cell death by neutralisation of anti-apoptotic proteins completely depended on BAX with a small contribution of BAK only in progenitors in the presence of LPS. A1 and NOXA appeared to stabilise each other at the posttranscriptional level suggesting direct binding. Co-immunoprecipitation experiments showed the binding of A1 to NOXA and BIM. Interaction between A1 and Noxa may indirectly prevent neutralisation and destabilization of MCL-1. Our findings suggest a unique role for A1 as a modulator of survival in the macrophage lineage in concert with MCL-1 and BCL-XL, especially in a pro-inflammatory environment.

Animals↗
PubMed2026

Genome mining and metabolomics unveil new napyradiomycin antibiotics from Streptomyces sp. 0H2M.

Napyradiomycins are a family of meroterpenoid natural products known for their promising antibiotic activities. In this study, four new napyradiomycins derivatives were identified, SF2415B4 (1), SF2415B5 (2), SF2415B6 (3), and SF2415B7 (4) from Streptomyces sp. 0H2M, alongside a known molecule, A80915A (5) through the synergy between genome mining and metabolomics analysis. Their structures were elucidated through a combination of spectroscopic and spectrometric analyses, including HRMS-ESI, NMR, and DP4+. Genome sequencing identified a putative biosynthetic gene cluster, and subsequent analyses revealed a distinct biosynthetic pathway with an unprecedented tailoring mechanism mediated by novel hydroxylases and halogenases. Biological assays demonstrated significant activity against Bacillus subtilis, Bacillus cereus and methicillin-resistant Staphylococcus aureus due to perturbation of cell membrane integrity, and minimum inhibitory concentration (MIC) values ranged from 0.24 to 30.7 μM. Additionally, in vitro cytotoxicity experiments indicated that compounds 2-5 very mildly inhibited the viability of human non-small cell lung cancer (NSCLC) cell line A549 in a concentration-dependent manner, with IC50 values of 16.7, 39.1, 65.0, and 32.8 μM, respectively. Moreover, they were shown to induce apoptosis and autophagy in A549 cells, evidenced by increased levels of cleaved PARP, decreased expression of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Survivin), and accumulation of LC3-II. These findings offer new insights into the natural product chemistry in Streptomyces and the pharmacology of napyradiomycin class antibiotics.

Streptomyces↗
PubMed2026

Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5 destabilization in prostate cancer.

Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.

Male↗
PubMed2026

Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.

Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins, which are characteristic pathological hallmarks of neurodegenerative diseases. As we previously found that microglia secreted factors impair neuronal autophagy and identified CCL3, CCL4 and CCL5 as causative chemokines, we screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against our expectations of identifying negative regulators, we found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro (SH-SY5Y, i3Neurons) and in vivo. Mechanistically, CXCL10 and CXCL13 promoted autophagy through a shared mechanism: cognate receptor stimulation led to downstream activation of JNK, which in turn phosphorylates BCL-XL, promoting its disassociation from BECN1. The freed BECN1 interacts with VPS34 to form the autophagy initiation complex, enhancing autophagosome formation and flux. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.

Journal Article↗
PubMed2025

Altered immune signatures in breast cancer lymph nodes with metastases revealed by spatial proteome analyses.

BACKGROUND: Metastasis to lymph nodes is strongly associated with reduced survival in breast cancer patients. To increase the understanding on how lymph node metastasis impairs the local immune response in affected lymph nodes, we here studied spatial proteomic changes of critical lymph node immune populations in uninvolved lymph nodes (UnLN) and paired lymph nodes with metastases (LNM) from five breast cancer patients. METHODS: The proteome was analyzed for cortical lymphocyte compartments, subcapsular sinus (SCS) and medullary sinus (MS) CD169+ macrophages, using the Digital Spatial Profiling (DSP) platform from NanoString. RESULTS: Our results identified a stable proteome of SCS CD169+ macrophages in LNM, with the exception for downregulation of the anti-apoptotic protein Bcl-xL and FAPα, but a clear reduction in numbers of SCS CD169+ macrophages in LNM. In contrast, the proteome of MS CD169+ macrophages, B-cell compartments and interfollicular T-cells showed altered immune signatures in LNM, indicating that the decline in SCS CD169+ macrophages coincide with a malfunction in the local, anti-tumor immune responses. CONCLUSIONS: The findings from our study support the notion that metastasis to lymph nodes in breast cancer patients modifies local immune responses. These changes may contribute to explain unsuccessful therapeutic responses, and thereby worsened prognosis, for breast cancer patients with LNM.

Breast Neoplasms↗