Biology subjects

Meiners, S.

Publications and source records attributed to Meiners, S..

7 recordsLinked to original sources

bioRxiv2026

SARS-CoV-2 (E)-protein induces rapid TLR2-mediated T cell activation in mouse lungs revealed by intravital lung microscopy

Mounting evidence indicates that T cells can operate in an innate-like mode challenging the classical description of T cells as strictly adaptive immune effectors. T cells can engage innate pattern recognition receptors to mount rapid but antigen-nonspecific responses to infection or cellular stress. This study observed that CD8+ T cells, and to a lesser extent also CD4+ T cells, responded to viral proteins in the mouse lung quickly in an innate-like fashion. We employed intravital lung microscopy to visualize infiltration of CD8+ T cells into the lung following intratracheal instillation of the SARS-CoV-2 envelope (E)-protein. Here, we demonstrate acute recruitment of CD8+ from the pulmonary microcirculation into the lung as early as 4 and 24 hours after (E)-protein instillation. The acute infiltration of CD8+ T cells was not observed in Tlr2-/- mice. Immunohistochemistry analysis of mouse lungs revealed T cell accumulation in nodular inflammatory foci (NIF) of the lung at perivascular regions and around large airways. Stimulating spleen-derived CD8+ T cells from wild-type mice with (E)-protein ex vivo in combination with cytokines or TCR agonists significantly upregulated CD69 and activated secretion of interferon (IFN){gamma} which was not observed with CD8+ T cells isolated from Tlr2-/- mice. These findings indicate rapid bystander activation of CD8+ T cells by the SARS-CoV-2 envelope (E)-protein that depends on (E)-protein sensing by TLR2. This innate-like CD8+ T cell response to SARS-CoV-2 (E)-protein may offer novel opportunities for diagnostic and therapeutic development, warranting further investigation.

immunology↗

bioRxiv2026

Local IFNγ signaling contributes to the regenerative decline of aged alveolar progenitor cells

The lungs are highly susceptible to chronic disease in advanced age, likely due to the uniquely compromised repair function of alveolar type II (AT2) cells, facultative progenitor cells that maintain the gas exchange surface. Using aging mouse models, single-cell sequencing, and ex vivo organoid assays, we found that homeostatic aged AT2 cells exhibited an Interferon {gamma} (IFN{gamma}) response associated with IFN{gamma}+ CD8+ T cells in tertiary lymphoid structures (TLS). Aged AT2 cells exhibit impaired regeneration in organoid assays and lost markers of an IFN{gamma} response outside the lung microenvironment, demonstrating that elevated local IFN{gamma} influences the state of AT2 cells. Neutralization of IFN{gamma} signaling and immunoproteasome knockout mice with attenuated IFN{gamma} levels partially rescued aged AT2 cell regeneration. Our findings demonstrate that local IFN{gamma} signaling in aging lungs actively represses alveolar regeneration, establishing chronic inflammatory signaling as a cause of age-related decline in the lung. Halting chronic inflammatory processes restored alveolar regeneration and may provide a means to improve lung health in old age.

cell biology↗

bioRxiv2025

Revealing the unexpected interplay between the Proteasome Activator PA200 and the immunoproteasome

The proteasome activator PA200 binds to the catalytic core of the proteasome, the 20S, and activates its proteolytic activities. The cellular function of PA200 is poorly understood and appears to be cell type and differentiation specific. Recent evidence suggests that PA200 not only binds to the standard 20S (s20S) proteasome but also to the specialized immunoproteasome (i20S) which plays a key role in anti-viral and anti-tumor immunity. We here investigated the interaction of PA200 and the immunoproteasome in detail. We show the very first cryo-EM structures of the singly- and doubly-capped i20S-PA200 complexes that revealed no major difference regarding the first binding event of PA200 to the i20S vs. the s20S. However, first PA200 binding triggered a subtle and long range allosteric bending of the i20S barrel which was not seen in the s20S-PA200 complexes. This resulted in major structural rearrangements in the opposite unbound ring - the displacement of atoms up to 5.4 [A] and the increase in its outer diameter - thereby increasing the occupancy of the second PA200 binding site. Mass photometry confirmed higher occupancy of PA200 to the i20S versus the s20S. Binding of PA200 to the i20S enhanced proteasomal activation compared to the s20S. Co-expression of PA200 and the i20S in cells and tissues, however, is restricted but their interaction is favored upon co-expression. The expression of PA200 and the catalytic subunits of the i20S is differentially regulated depending on the cellular context. Our data also suggest that PA200 has the potential to regulate i20S gene expression whereas the i20S has no effects on PA200 expression. Overall, this work sheds new light on the interaction of PA200 with the i20S from a structural, mechanistic and cellular point of view. Importantly, we identify PA200 as a key regulator of the i20S whenever PA200 and the catalytic subunits of the i20S are co-expressed in the same cell.

biochemistry↗

bioRxiv2024

The proteasome activator PA200 regulates tumor cell invasion

Proteasome activator 200 (PA200) is upregulated in non-small cell lung cancer (NSCLC) and linked to poor prognosis. We previously demonstrated that the overexpression of PA200 in NSCLC is associated with immune evasion and reduced responsiveness to immune checkpoint inhibitors. The cell autonomous function of PA200 in cancer growth, however, is not solved. We here demonstrate that deletion of PA200 in two distinct lung cancer cell lines induced cell-specific alterations in proteasome composition and activities with a minor direct impact on overall proteasome activity. Deficiency of PA200 in lung cancer cells did not consistently alter tumor cell growth in vitro and in vivo. However, we observed concerted inhibition of tumor cell migration and invasion with conserved downregulation of the integrin ITGB3 and transcriptional dysregulation of multiple cell adhesion and ECM regulators. Our transcriptome profiling revealed a striking disparity in the transcriptional response to PA200 deletion in the two lung cancer cell lines. Together with our PA200 interactome analysis that uncovered an unexpected cell-dependent profile of PA200-interacting proteins, our data indicate that the function of PA200 is cell-specific and depends on the cellular context. In conclusion, we here demonstrate that PA200 cell-autonomously regulates the invasive capacities of tumor cells thereby potentially promoting lung cancer spread and metastasis formation. This mechanism might add to PA200-related immune evasion and may contribute to the observed poor prognosis of PA200-overexpressing lung cancer patients.

cancer biology↗

bioRxiv2021

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumors responses to immunotherapy. For example, immunoproteasomes - a subset of proteasomes induced by inflammatory signals - may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/464690v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e87910org.highwire.dtl.DTLVardef@641843org.highwire.dtl.DTLVardef@175092corg.highwire.dtl.DTLVardef@ad34c2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMapping the degradation landscape in Non-Small Cell Lung Cancer (NSCLC) uncovers altered proteasome activity and composition C_LIO_LIProteasome regulator PSME4 plays an anti-inflammatory role in NSCLC by attenuating immunoproteasome activity C_LIO_LIPSME4 restricts tumor antigen presentation and cytokine secretion, defining a cold tumor environment C_LIO_LIPSME4 drives tumor immune evasion and is associated with resistance to immunotherapy C_LI

cancer biology↗

bioRxiv2020

Adaptive mitochondrial regulation of the proteasome

The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Regulation of proteasome function by mitochondrial metabolism, however, is unknown. Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome in the absence of oxidative stress. Impaired respiratory complex I function leads to metabolic reprogramming of the Krebs cycle and deficiency in aspartate. Aspartate supplementation activates assembly and activity of 26S proteasomes via transcriptional activation of the proteasome assembly factors p28 and Rpn6. This metabolic adaptation of 26S proteasome function involves sensing of aspartate via the mTORC1 pathway. Metformin treatment of primary human cells similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, respiratory dysfunction conferred resistance towards the proteasome inhibitor Bortezomib. Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.

cell biology↗

bioRxiv2020

Organ-restricted vascular delivery of nanoparticles for lung cancer therapy

Nanomedicines hold immense promise for a number of devastating diseases due to the ability to custom-design both the carrier and cargo. However, their clinical implementation has been hampered by physicochemical and biological barriers and off-target deposition which impair cell specific targeting, especially in internal organs. This study reports a new delivery approach using organ-restricted vascular delivery to allow for direct administration and recirculation of stimuli-responsive nanoparticles to promote cellular uptake into an organ of interest. Using this technique, nanoparticles reach the interior of dense tumors and are selectively taken up by lung cancer cells. Importantly, this surgical approach is essential as the same nanoparticles do not reach lung tumor cells upon systemic or intratracheal administration. Organ-restricted vascular delivery thus opens up new avenues for optimized nanotherapies for cancer and other diseases.

pharmacology and toxicology↗