Cell Discovery最新文献

PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.

Mammalian organs and tissues are composed of heterogeneously distributed cells, which interact with each other and the extracellular matrix surrounding them in a spatially defined way. Therefore, spatially resolved gene expression profiling is crucial for determining the function and phenotypes of these cells. While genome mutations and transcriptome alterations act as drivers of diseases, the proteins that they encode regulate essentially all biological functions and constitute the majority of biomarkers and drug targets for disease diagnostics and treatment. However, unlike transcriptomics, which has a recent explosion in high-throughput spatial technologies with deep coverage, spatial proteomics capable of reaching bulk tissue-level coverage is still rare in the field, due to the non-amplifiable nature of proteins and sensitivity limitation of mass spectrometry (MS). More importantly, due to the limited multiplexing capability of the current proteomics methods, whole-tissue slice mapping with high spatial resolution requires a formidable amount of MS matching time. To achieve spatially resolved, deeply covered proteome mapping for centimeter-sized samples, we developed a sparse sampling strategy for spatial proteomics (S4P) using computationally assisted image reconstruction methods, which is potentially capable of reducing the number of samples by tens to thousands of times depending on the spatial resolution. In this way, we generated the largest spatial proteome to date, mapping more than 9000 proteins in the mouse brain, and discovered potential new regional or cell type markers. Considering its advantage in sensitivity and throughput, we expect that the S4P strategy will be applicable to a wide range of tissues in future studies.

The emerging field of epitranscriptomics is reshaping our understanding of post-transcriptional gene regulation in inflammatory diseases. N⁴-acetylcytidine (ac⁴C), the only known acetylation modification in RNA catalyzed by N-acetyltransferase 10 (NAT10), is known to enhance mRNA stability and translation, yet its role in inflammatory bowel disease (IBD) remains unclear. In this study, we discovered that Nat10 expression correlates with inflammatory and apoptotic pathways in human ulcerative colitis CD4⁺ T cells. Our further analysis revealed that the deficiency of NAT10 led to a disruption of T cell development at steady state, and identified a pivotal role for NAT10 in preserving the pathogenicity of naïve CD4⁺ T cells to induce adoptive transfer colitis. Mechanistically, the lack of NAT10 triggers the diminished stability of the anti-apoptotic gene BCL2-associated athanogene 3 (Bag3), initiating a cascade of events that includes the upregulation of apoptosis-related genes and an accelerated rate of apoptosis in T cells. Our findings reveal a previously unrecognized role of the NAT10-ac⁴C-Bag3 axis in preserving T cell balance and suggests that targeting RNA ac⁴C modification could be a promising therapeutic approach for IBD.

In mammalian cells, endoplasmic reticulum (ER) passively releases Ca²⁺ under steady state, but channels involved remain elusive. Here, we report that TMEM41B, an ER-resident membrane protein critical for autophagy, lipid metabolism, and viral infection, functions as an ER Ca²⁺ release channel. Biochemically, purified recombinant TMEM41B forms a concentration-dependent Ca²⁺ channel in single-channel electrophysiology assays. Cellularly, TMEM41B deficiency causes ER Ca²⁺ overload, while overexpression of TMEM41B depletes ER Ca²⁺. Immunologically, ER Ca²⁺ overload leads to upregulation of IL-2 and IL-7 receptors in naive T cells, which in turn increases basal signaling of JAK-STAT, AKT-mTOR, and MAPK pathways. This dysregulation drives TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca²⁺ overload also downregulates CD5, lowering the activation threshold of TMEM41B-deficient T cells and leading to heightened T cell responses during infections. In summary, we identify TMEM41B as a concentration-dependent ER Ca²⁺ release channel, revealing an unexpected role of ER Ca²⁺ in naive T cell quiescence and responsiveness.

Competitive interactions are pervasive within biological populations, where individuals engage in fierce disputes over vital resources for survival. Before the establishment of a social hierarchy within the population, this competition becomes even more intense. Historical experiences of competition significantly influence the competitive performance; individuals with a history of persistent loss are less likely to initiate attacks or win escalated contests. However, it remains unclear how historical loss directly affects the evolution of mental processes during competition and alters responses to ongoing competitive events. Here, we utilized a naturalistic food competition paradigm to track the competitive patterns of mutually unfamiliar competitors and found that a history of loss leads to reduced competitive performance. By tracking the activity of ventral hippocampal neuron ensembles, we identified clusters of neurons that responded differently to behavioral events during the competition, with their reactivity modulated by previous losses. Using a Recurrent Switch Linear Dynamical System (rSLDS), we revealed rotational dynamics in the ventral hippocampus (vHPC) during food competition, where different discrete internal states corresponded to different behavioral strategies. Moreover, historical loss modulates competitive behavior by remodeling the characteristic attributes of this rotational dynamic system. Finally, we found that an evolutionarily conserved glutamate receptor-associated protein, glutamate receptor-associated protein 1 (Grina), plays an important role in this process. By continuously monitoring the association between the attributes of the dynamic system and competitiveness, we found that restoring Grina expression effectively reversed the impact of historical loss on competitive performance. Together, our study reveals the rotational dynamics in the ventral hippocampus during competition and elucidates the underlying mechanisms through which historical loss shapes these processes.

Drug-induced liver injury (DILI) is the leading cause of acute liver failure and poses a significant clinical challenge in both diagnosis and treatment. Serine synthesis pathway (SSP) links glycolysis to one-carbon cycle and plays an important role in cell homeostasis by regulating substance synthesis, redox homeostasis and gene expression. However, the regulatory mechanism of SSP in DILI remains unclear. Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in SSP. Here we show that during DILI, mitogen-activated protein kinase 13 (MAPK13) is activated and then phosphorylates PHGDH at serine 371 upon oxidative stress, which triggers PHGDH protein degradation via chaperone-mediated autophagy (CMA) pathway. PHGDH degradation suppresses SSP and glutathione production, thereby exacerbating DILI and cholestatic liver injury. Importantly, both MAPK13 inhibition and dietary serine supplementation ameliorates these liver injuries. Our finding demonstrates a unique regulatory mechanism of SSP, in which MAPK13 phosphorylates PHGDH and promotes its CMA degradation, establishes its critical role in DILI and cholestatic liver injury, and highlights the therapeutic potential of MAPK13 inhibitor or dietary serine to treat these liver injuries.

Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations' metabolic health.