Cell Discovery最新文献

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

HOIP, an RBR-type E3 ligase and the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), plays crucial roles in various cellular processes, including the NF-κB signaling pathway. The E3 activity of HOIP can be inhibited by the kinase STK4-mediated phosphorylation, although the mechanism is poorly understood. In this study, using biochemical, mass spectrometry and structural approaches, we systemically characterize the association of STK4 with HOIP, and unveil that STK4 can directly bind to the RING2-LDD module of HOIP through its kinase domain. The determined crystal structure of STK4 in complex with HOIP RING2-LDD not only elucidates the detailed binding mechanism of STK4 with HOIP, but also uncovers, for the first time, a unique binding mode of STK4 with its substrate. Moreover, we reveal that STK4 can directly phosphorylate the T786 residue of HOIP that is located in the allosteric ubiquitin-binding site of HOIP. Importantly, the phosphorylation of HOIP T786 mediated by STK4 can block the binding of ubiquitin to the allosteric site of HOIP, thereby attenuating the E3 activity of HOIP. In all, our findings provide mechanistic insights into the interaction between STK4 and HOIP as well as the negative regulation of HOIP's E3 activity by STK4-mediated phosphorylation, which are valuable for further understanding the regulatory modes of RBR-type E3 ligases.

Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.

In the evolutionary arms race between bacteria and viruses, retrons have emerged as distinctive antiphage defense systems. Here, we elucidate the structure and function of Retron-Eco2, which comprises a non-coding RNA (ncRNA) that encodes multicopy single-stranded DNA (msDNA, a DNA‒RNA hybrid) and a fusion protein containing a reverse transcriptase (RT) domain and a topoisomerase-primase-like (Toprim) effector domain. The Eco2 msDNA and RT-Toprim fusion protein form a 1:1 stoichiometric nucleoprotein complex that further assembles into a trimer (msDNA:RT-Toprim ratio of 3:3) with a distinctive triangular configuration. The RNA portion of the msDNA in one protomer closely intertwines around the RT domain of an adjacent protomer, mediating the formation of this self-inhibitory assembly. Upon activation, the Toprim effector domain exhibits RNase activity, degrading RNA to arrest phage replication. We further reveal that phage mutants evading Eco2-mediated defense harbor mutations in the endonuclease IV-like protein DenB, underscoring DenB's critical role in triggering the activation of this system. Together, these findings provide key structural and functional insights into Retron-Eco2, laying the groundwork for harnessing its potential in biotechnology and synthetic biology applications.

Brain parenchymal metastases (BM) and leptomeningeal metastases (LM) represent distinct subtypes of central nervous system metastases (CNSm) from lung cancer, posing significant clinical challenges. The local immune landscape of LM remains elusive. Herein, we utilized single-cell RNA sequencing to build a cell atlas of LM, and systematically examine the immune profiling and cell heterogeneity between BM and LM. Our analysis reveals that BM has more CXCL9⁺ macrophages, CXCL13⁺CD4⁺ T cells and B cells than LM, exhibiting the presence of tertiary lymphoid (TLS) structures, which is associated with a favorable response to tyrosine kinase inhibitors (TKI). Conversely, a remarkably immunosuppressive tumor microenvironment (TME) is detected in LM, characterized by lymphocyte depletion and a concurrent enrichment of SPP1⁺ macrophages, compared to BM. Furthermore, we identified significant blood-brain barrier (BBB) cell discrepancies between BM and LM, and substantial phenotypic reprogramming of BBB cells in CNSm. This reprogramming encompassed alterations in transporter gene expression, extracellular matrix production and dysregulated cell-cell interactions, potentially contributing to the metastatic process. In summary, this study highlights the divergent cellular and molecular landscapes of BM vs LM, offering critical insights into potential therapeutic targets and informing the development of improved treatment strategies for non-small cell lung cancer patients with CSNm.

Disuse-induced bone loss occurs in long-term bed-ridden patients and in astronauts during spaceflight. The underlying mechanisms are poorly understood. In a rodent model of disuse-induced bone loss (called hindlimb unloading (HU)), we observed that decreased numbers of leptin receptor (LepR) positive mesenchymal stem cells (MSCs) in adult bone marrow, contribute to bone loss. MicroRNA-337-3p (miR-337) was upregulated in MSCs upon HU and inhibited MSC proliferation by directly targeting IRS-1 to suppress the PI3kinase-Akt-mTOR pathway. Piezo1 was the upstream receptor for sensing mechanical stress and regulated miR-337 through the Hippo-YAP signaling pathway. Remarkably, the knockout of miR-337 significantly attenuated HU-induced, but not ovariectomy-induced, bone loss by increasing MSC proliferation and osteogenesis. Finally, the transplantation of miR-337^-/- MSCs into wild-type HU mice was sufficient to mitigate bone loss. These findings reveal the cellular and molecular mechanisms underlying disuse-induced bone loss and highlight a feasible therapeutic strategy to prevent disuse- or microgravity-induced bone loss on Earth and during spaceflight.