IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy.

Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

Microbial diversity and their extracellular enzyme activities among different soil particle sizes in mossy biocrust under N limitation in the southeastern Tengger Desert, China.

Introduction: Mossy biocrust represents a stable stage in the succession of biological soil crust in arid and semi-arid areas, providing a microhabitat that maintains microbial diversity. However, the impact of mossy biocrust rhizoid soil and different particle sizes within the mossy biocrust layer and sublayer on microbial diversity and soil enzyme activities remains unclear. Methods: This study utilized Illumina MiSeq sequencing and high-throughput fluorometric technique to assess the differences in microbial diversity and soil extracellular enzymes between mossy biocrust rhizoid soil and different particle sizes within the mossy biocrust sifting and sublayer soil. Results: The results revealed that the total organic carbon (TOC), total nitrogen (TN), ammonium (NH4+) and nitrate (NO3-) in mossy biocrust rhizoid soil were the highest, with significantly higher TOC, TN, and total phosphorus (TP) in mossy biocrust sifting soil than those in mossy biocrust sublayer soil. Extracellular enzyme activities (EAAs) exhibited different responses to various soil particle sizes in mossy biocrust. Biocrust rhizoid soil (BRS) showed higher C-degrading enzyme activity and lower P-degrading enzyme activity, leading to a significant increase in enzyme C: P and N: P ratios. Mossy biocrust soils were all limited by microbial relative nitrogen while pronounced relative nitrogen limitation and microbial maximum relative carbon limitation in BRS. The diversity and richness of the bacterial community in the 0.2 mm mossy biocrust soil (BSS0.2) were notably lower than those in mossy biocrust sublayer, whereas the diversity and richness of the fungal community in the rhizoid soil were significantly higher than those in mossy biocrust sublayer. The predominant bacterial phyla in mossy biocrust were Actinobacteriota, Protebacteria, Chloroflexi, and Acidobacteriota, whereas in BSS0.2, the predominant bacterial phyla were Actinobacteriota, Protebacteria, and Cyanobacteria. Ascomycota and Basidiomycota were dominant phyla in mossy biocrust. The bacterial and fungal community species composition exhibited significant differences. The mean proportions of Actinobacteriota, Protebacteria, Chloroflexi, Acidobacteriota, Acidobacteria, Cyanobacteria, and Bacteroidota varied significantly between mossy biocrust rhizoid and different particle sizes of mossy biocrust sifting and sublayer soil (p < 0.05). Similarly, significant differences (p < 0.05) were observed in the mean proportions of Ascomycota, Basidiomycota, and Glomeromycota between mossy biocrust rhizoid and different particle sizes within the mossy biocrust sifting and sublayer soil. The complexity and connectivity of bacterial and fungal networks were higher in mossy biocrust rhizoid soil compared with different particle sizes within the mossy biocrust sifting and sublayer soil. Discussion: These results offer valuable insights to enhance our understanding of the involvement of mossy biocrust in the biogeochemical cycle of desert ecosystems.

The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity.

In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.