Science China Life Sciences最新文献

Sound pollution (noise) is an increasing environmental concern, particularly associated with neurological and neurobehavioral abnormalities. However, the molecular mechanisms underlying noise-induced neural damage remain unclear. In this study, we conducted transcriptional profiling of zebrafish to investigate the mechanisms underlying acoustic stimulation (1,000 Hz, 130 dB). RNA sequencing and subsequent experiments revealed that TRPV1 is an important mediator of noise-induced neural damage in HuC(elavl3)-GFP transgenic zebrafish. The results demonstrated that inhibiting TRPV1 significantly mitigated noise-induced neural damage in zebrafish with trpv1 gene RNAi and in mice with Trpv1 knockout (Trpv1^-/-). Specifically, TRPV1 antagonism significantly reduced neural damage in zebrafish and mice under noise exposure. Furthermore, activated TRPV1 could induce endoplasmic reticulum stress, leading to apoptosis and resulting in neural damage in mice and HEK293T cells. The findings of this study not only enhance our understanding of the molecular mechanisms underlying sound-induced neural damage but also highlight a novel target for drug intervention.

In eukaryotes, N-glycosylation is a complex, multistep process in which the core subunit of oligosaccharyltransferase, Staurosporine and Temperature Sensitive 3A (STT3A), plays a critical role in the catalytic activity of the oligosaccharyltransferase (OST) complex. We found that the PsSTT3A gene plays a critical role in the viability of Phytophthora sojae (P. sojae). Furthermore, full PsSTT3A function was crucial to mycelial growth, sporangium production, zoospore production, and pathogenicity, as determined by gene silencing experiments. PsSTT3A is, itself, a highly N-glycosylated protein with six consensus NXS/T (Asn-X-Ser/Thr) motifs and one novel NS motif. However, the N-glycosylation sites on PsSTT3A that are required to support the development and virulence of P. sojae have been uncertain. Here, we demonstrated that glycosylation of site N593 is essential for normal mycelial growth and virulence in P. sojae. Furthermore, endoplasmic reticulum (ER) homeostasis was disrupted by the mutation of N593. N593A mutations reduced the stability of the elicitin PsSOJ2A, an N-glycoprotein, in gene replacement transformations. Our study reveals the functional significance of N-glycosylation of PsSTT3A in the development and infection cycles of P. sojae, demonstrating that targeting of PsSTT3A may be a promising strategy for developing new mode of action fungicides.

The lysosome is transformed from a major degradative site to a dynamic regulator of cellular homeostasis. Cancer cells with altered redox environments could be exploited as potential targets for cancer therapy. The thioredoxin (Trx) system, which includes thioredoxin reductases (TrxRs), is a promising target for cancer drug development. Here, by identifying the natural product isowalsuranolide (Hdy-7), we showed that lysosomal biogenesis and autophagy are elicited by Hdy-7 via the inhibition of TrxRs. The attenuation of cellular TrxR activity led to the accumulation of ROS, which are indispensable for p53 activation and subsequent lysosomal biogenesis mediated by the transcription factor TFEB/TFE3. Knockdown of TrxR1/2 led to activation of TFEB/TFE3, thereafter increasing lysosomal biogenesis. Treatment with the ROS scavenger NAC or knockdown of p53 or SESN2 led to attenuation of the nuclear translocation of TFEB/TFE3, lysosomal biogenesis, and autophagic flux, suggesting that the TrxR1/2-p53-TFEB/TFE3 axis plays a role in maintaining lysosomal homeostasis under stress conditions other than starvation. Surprisingly, pharmacological inhibition or genetic ablation of autophagy prevented Hdy-7-induced cell death, suggesting that Hdy-7-induced autophagy is detrimental to cancer cells. Our study revealed that Hdy-7 induces ROS-mediated lysosomal biogenesis and retards cell growth by targeting TrxR1/2. This study highlights the lysosome as a regulatory hub for cellular homeostasis and as an attractive therapeutic target for a variety of lysosome-related diseases, including cancer.

As a common disease in human life, fungal infection poses a serious threat to human life and health. Moreover, owing to the rapid development of the immune escape mechanisms of fungi and the emergence of new drug-resistant fungi, existing therapeutic drugs are no longer able to meet the treatment needs of patients. In particular, the World Health Organization (WHO) published the first Fungal Priority Pathogens List (FPPL) in 2022, further emphasizing that we need to pay more attention to invasive fungal infections. In addition, the WHO has called for increased global investment in fungal infections and the development of antifungal drugs. In this review, we introduce the mechanism by which innate immune cell PRRs recognize fungal pathogen PAMPs, the role of adaptive immune cells in antifungal immunity, fungal infections caused by immune deficiencies, and the latest research progress in immune-based fungal therapies.

Atrial fibrillation (AF) is the most common arrhythmia, which is tightly associated with the abnormal expression and function of ion channels in the atrial cardiomyocytes. N⁶-methyladenosine (m⁶A), a widespread chemical modification in eukaryotic mRNA, is known to play a significant regulatory role in the pathogenesis of heart disease. However, the significance of m⁶A regulatory proteins in the onset of AF remains unclear. Here, we demonstrate that the m⁶A reader protein YTHDF2 regulates atrial electrical remodeling and AF onset by modulating the Cav1.2 expression. Firstly, YTHDF2 expression was selectively upregulated in rat atrial cardiomyocytes with AF. Secondly, YTHDF2 knockout reduced AF susceptibility in mice. Thirdly, the knockout of YTHDF2 increased Cav1.2 protein levels in an m⁶A-in-dependent manner, ultimately prolonging the atrial myocardial refractory period, a critical electrophysiological substrate for the onset of AF. Fourthly, the N-terminal domain of YTHDF2 was identified as critical for Cacna1c mRNA translation regulation. Overall, our findings unveil that YTHDF2 can alter Cav1.2 protein expression in an m⁶A-independent manner, thereby facilitating the onset of AF. Our study suggests that YTHDF2 may be a potential intervention target for AF.