bims-polyam 2024-12-15 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2024–12–15
six papers selected by
Sebastian J. Hofer, University of Graz

Efficient production of spermidine from Bacillus amyloliquefaciens by enhancing synthesis pathway, blocking degradation pathway and increasing precursor supply.
Spermidine alleviates thymopoiesis defects and aging of the peripheral T-cell population in mice after radiation exposure.
The putative polyamine transporter Shp2 facilitates phosphate export in an Xpr1-independent manner and contributes to high phosphate tolerance.
Visualizing the modification landscape of the human 60S ribosomal subunit at close to atomic resolution.
Spermidine alleviates diabetic periodontitis by reversing human periodontal ligament stem cell senescence via mitophagy.
Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma.

J Biotechnol. 2024 Dec 06. pii: S0168-1656(24)00321-3. [Epub ahead of print]398 87-96

Efficient production of spermidine from Bacillus amyloliquefaciens by enhancing synthesis pathway, blocking degradation pathway and increasing precursor supply.

Ziyue Zhao, Ailing Guo, Dian Zou, Zhou Li, Xuetuan Wei.

  Spermidine has broad application potential in food, medicine and other fields. In this study, a novel Bacillus amyloliquefaciens cell factory was constructed for production of spermidine from renewablebiomass resources. Firstly, the speB gene was found to be optimal for synthesis of spermidine, and the function of SpeB was explained by amino acid sequence analysis and molecular docking. By replacing the native promoter of the speEB operon with the P43, the synthesis of spermidine was significantly enhanced in B. amyloliquefaciens HSPM1-P43speEB. After knockout of the genes yobN and bltD associated with spermidine degradation, the spermidine titer of the strain HSPM2 was further improved to 115.96 mg/L, increased by 108 % compared to HSPM1-P43speEB. Subsequently, the titer of spermidine was further increased to 277.47 mg/L through enhancing the supply of the precursor methionine by overexpression of speD. Finally, the renewable biomass resources, xylose and feather meal were optimized to produce spermidine, and the maximum titer is up to 588.10 mg/L after optimization. In conclusion, an efficient spermidine producing B. amyloliquefaciens was constructed through combinatorial metabolic engineering strategies, and the sustainable production of spermidine was achieved using the biomass resources of xylose and feather meal.

Keywords:  Bacillus amyloliquefaciens; Combinatorial metabolic engineering; Feather meal; Spermidine; Xylose

DOI:  https://doi.org/10.1016/j.jbiotec.2024.12.001
Exp Gerontol. 2024 Dec 04. pii: S0531-5565(24)00292-4. [Epub ahead of print] 112646

Spermidine alleviates thymopoiesis defects and aging of the peripheral T-cell population in mice after radiation exposure.

Kengo Yoshida, Zhenqiu Liu, Yoshiko Kubo, Masahiko Miura, Mika Yamaoka, Hiroko Nagamura, Munechika Misumi, Yoichiro Kusunoki.

  The T cell aging process can be modified by genotoxic factors, including ionizing radiation, and metabolic controls, such as caloric restriction; the former accelerates and the latter retards the process. However, the mechanisms by which these systemic factors interact to cause T cell aging remain unclear. This study investigated the naïve T-cell pool, thymic cellularity, and transcriptome in mice irradiated with 3.8 Gy at 5 weeks of age and treated 13 months later with 30 mM spermidine (SPD), a metabolism regulator. The number of conventional naïve CD4 and CD8 T cells in the peripheral blood decreased 14 months after irradiation whereas the number of virtual memory naïve T cells, which increased with age, further increased by irradiation. However, these radiation-related changes were not significant in similarly irradiated mice that were subsequently treated with SPD. The numbers of total, double-positive, and single-positive thymocytes were decreased by irradiation, whereas none were decreased in the irradiated mice treated with SPD. RNA sequencing of thymus cells revealed 803 upregulated genes in irradiated mice compared with those in non-irradiated control mice, with these genes enriched in leukocyte activation and inflammatory cytokine production. However, only 22 genes were upregulated in irradiated and SPD-treated mice, suggesting a reversal of many radiation-induced gene expression changes. These findings suggest that SPD may alleviate radiation-induced acceleration of T-cell aging, particularly by mitigating reduced thymopoiesis and inflammation. Further research is warranted to explore the rejuvenating potential of SPD and its mechanisms of action in accelerated T-cell aging.

Keywords:  Radiation; Spermidine; T-cell aging

DOI:  https://doi.org/10.1016/j.exger.2024.112646
J Biol Chem. 2024 Dec 09. pii: S0021-9258(24)02558-4. [Epub ahead of print] 108056

The putative polyamine transporter Shp2 facilitates phosphate export in an Xpr1-independent manner and contributes to high phosphate tolerance.

Tochi Komamura, Tomoki Nishimura, Naoki Ohta, Masahiro Takado, Tomohiro Matsumoto, Kojiro Takeda.

Phosphate (Pi) homeostasis at the cellular level is crucial, requiring coordinated Pi uptake, storage, and export. However, the regulatory mechanisms, particularly those governing Pi export, remain elusive, despite their relevance to human diseases like primary familial brain calcification. While Xpr1, conserved across eukaryotes, is the only known Pi exporter, the existence of additional Pi exporting factors is evident; however, these factors have been poorly characterized. Using the fission yeast Schizosaccharomyces pombe as a model, we have aimed to better understand cellular Pi homeostasis mechanisms. Previously, we showed three Pi regulators with SPX domains to be critical: Pqr1 (Pi uptake restrictor), Xpr1/Spx2, and the VTC complex (polyphosphate synthase). SPX domains bind to inositol pyrophosphate, modulating Pi regulator functions. The double mutant Δpqr1Δxpr1 hyper-accumulates Pi and undergoes cell death under high Pi conditions, indicating the necessity of both Pi uptake restriction and export. Notably, Δpqr1Δxpr1 exhibits residual Pi export activity independent of Xpr1, suggesting the presence of unidentified Pi exporters. To uncover these cryptic Pi exporters and regulators of Pi homeostasis, we conducted suppressor screening for high Pi hypersensitivity in Δpqr1Δxpr1. Among the eight suppressors identified, Shp2, a plasma-membrane protein, showed Pi export-facilitating activity in an Xpr1-independent manner, supporting cell proliferation at high Pi. The present results provide the first evidence for Pi export facilitator other than the established Xpr1, unprecedented in eukaryotes. As Shp2 is orthologous to the budding yeast Tpo1, a spermidine/polyamine transporter, a potential link between Pi homeostasis and polyamine metabolism can be speculated.

DOI: https://doi.org/10.1016/j.jbc.2024.108056
Nucleic Acids Res. 2024 Dec 10. pii: gkae1191. [Epub ahead of print]

Visualizing the modification landscape of the human 60S ribosomal subunit at close to atomic resolution.

Franziska Wiechert, Anett Unbehaun, Thiemo Sprink, Helena Seibel, Jörg Bürger, Justus Loerke, Thorsten Mielke, Christoph A Diebolder, Magdalena Schacherl, Christian M T Spahn.

Chemical modifications of ribosomal RNAs (rRNAs) and proteins expand their topological repertoire, and together with the plethora of bound ligands, fine-tune ribosomal function. Detailed knowledge of this natural composition provides important insights into ribosome genesis and function and clarifies some aspects of ribosomopathies. The discovery of new structural properties and functional aspects of ribosomes has gone hand in hand with cryo-electron microscopy (cryo-EM) and its technological development. In line with the ability to visualize atomic details - a prerequisite for identifying chemical modifications and ligands in cryo-EM maps - in this work we present the structure of the 60S ribosomal subunit from HeLa cells at the very high global resolution of 1.78 Å. We identified 113 rRNA modifications and four protein modifications including uL2-Hisβ-ox216, which stabilizes the local structure near the peptidyl transferase centre via an extended hydrogen-bonding network. We can differentiate metal ions Mg2+ and K+, polyamines spermine, spermidine and putrescine and identify thousands of water molecules binding to the 60S subunit. Approaching atomic resolution cryo-EM has become a powerful tool to examine fine details of macromolecular structures that will expand our knowledge about translation and other biological processes in the future and assess the variability of the chemical space due to differences between species/tissues or varying physicochemical environment.

DOI: https://doi.org/10.1093/nar/gkae1191
Free Radic Biol Med. 2024 Dec 08. pii: S0891-5849(24)01120-1. [Epub ahead of print]227 379-394

Spermidine alleviates diabetic periodontitis by reversing human periodontal ligament stem cell senescence via mitophagy.

Yi Zhou, Danlei Wang, Qianxuan Xiao, Lu Ma, Huiqing Gou, Yiwen Ru, Jingqi Tang, Xuanwen Xu, Xu Chen, Wen Sun, Lu Li, Yan Xu.

  Type 2 Diabetes Mellitus (T2DM) exacerbates periodontal disease lesions, and human periodontal ligament stem cells (PDLSCs) depletion may be the key to periodontal healing impair by T2DM. This study aims to explore the mechanism of PDLSCs depletion in diabetes periodontitis (DP). Firstly, we observed aggravated periodontal destruction in the DP animal model, accompanied by oxidative damage and accumulation of senescent cells. In the high-glucose inflammatory environment in vitro, we revealed that PDLSCs underwent senescence, oxidative stress, mitochondrial dysfunction, and activation of cGAS-STING signaling pathway triggered by mitochondrial DNA. Lineage tracing confirmed that SPD recruited Tdtomato-Gli1+ PDLSCs to the damaged area and alleviated periodontal destruction in DP models. Evidence in vitro further showed that SPD inhibited PDLSCs senescence and oxidative stress, enhanced mitochondrial function, reduced membrane permeability transition pore opening, and reduced DNA leakage, which blocked the STING activation. Mechanistically, SPD reduced STING-TBK1 phosphorylation by scavenging mitochondrial-derived dsDNA in a mitophagy-dependent manner, its therapeutic effect was abolished by incorporation of cGAMP, a STING activator. In summary, our study reveals the mechanism of PDLSCs depletion due to excessive oxidative damage in the DP environment. Local injection of SPD reactivates mitophagy, recruits Gli1+ stem cells by inhibiting STING activation for periodontal regeneration.

Keywords:  Cell senescence; Mitophagy; Periodontal ligament stem cells; Periodontitis; Spermidine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.016
Cell Death Differ. 2024 Dec 10.

Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma.

Yining Sun, Peitao Zhou, Junying Qian, Qin Zeng, Guangyan Wei, Yongsheng Li, Yuechen Liu, Yingjie Lai, Yizhi Zhan, Dehua Wu, Yuan Fang.

Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via "subcutaneous" and "orthotopic" HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.

DOI: https://doi.org/10.1038/s41418-024-01409-z