bims-polyam 2022-08-21 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–08–21
seven papers selected by
Sebastian J. Hofer, University of Graz

Helping the helpers: polyamines help maintain helper T-cell lineage fidelity.
Herpesvirus-induced spermidine synthesis and eIF5A hypusination for viral episomal maintenance.
Engineering the Surface Properties of DNA Nanostructures by Tuning the Valency of Assembling Species for Biomedical Applications.
POLYAMINES AS NEW POTENTIAL BIOMARKERS FOR DIFFERENTIAL DIAGNOSIS OF PROSTATE CANCER AND ESTIMATION OF ITS AGGRESSIVENESS.
LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages.
Loss-of-function variants in SAT1 cause X-linked childhood-onset systemic lupus erythematosus.
Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study.

Immunometabolism (Cobham). 2022 Jul;4(3): e00002

Helping the helpers: polyamines help maintain helper T-cell lineage fidelity.

Tracy Murray Stewart, Cassandra E Holbert, Robert A Casero.

  The awareness that polyamines play a critical role in immune system regulation and function is coming into focus as the biological systems and analytical tools necessary to evaluate their roles have become available. Puleston et al have recently demonstrated that polyamine metabolism plays a central role in helper T-cell lineage determination through the production of the translational cofactor hypusinated eIF5A and faithful epigenetic regulation through proper histone acetylation. Their findings add to the rapidly growing body of data implicating properly controlled polyamine metabolism as essential for a normally functioning immune system.

Keywords:  T cells; histone acetylation; hypusine; immune; polyamines; spermidine; spermine

DOI:  https://doi.org/10.1097/IN9.0000000000000002
Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01051-8. [Epub ahead of print]40(7): 111234

Herpesvirus-induced spermidine synthesis and eIF5A hypusination for viral episomal maintenance.

Un Yung Choi, Jae Jin Lee, Angela Park, Kyle L Jung, Shin-Ae Lee, Youn Jung Choi, Hye-Ra Lee, Chih-Jen Lai, Hyungjin Eoh, Jae U Jung.

  Spermidine is essential for cellular growth and acts as a prerequisite of hypusination, a post-translational modification of eukaryotic initiation factor 5A (eIF5A), allowing the translation of polyproline-containing proteins. Here, we show that oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) increases spermidine synthesis and eIF5A hypusination to enhance expression of polyproline-containing latency-associated nuclear antigen (LANA) for viral episomal maintenance. KSHV upregulates intracellular spermidine levels by dysregulating polyamine metabolic pathways in three-dimensional (3D) culture and 2D de novo infection conditions. Increased intracellular spermidine leads to increased eIF5A hypusination, ultimately enhancing LANA expression. In contrast, inhibition of spermidine synthesis or eIF5A hypusination alleviates LANA expression, decreasing viral episomal maintenance and KSHV-infected cell proliferation in vitro and in vivo, which is reversed by spermidine supplement. This demonstrates that KSHV hijacks spermidine synthesis and eIF5A hypusination pathways to enhance LANA expression for viral episomal maintenance, suggesting polyamine metabolism and eIF5A hypusination as therapeutic targets for KSHV-induced tumorigenesis.

Keywords:  CP: Microbiology; KSHV; Kaposi’s sarcoma-associated herpesvirus; LANA; cancer metabolism; eIF5A hypusination; polyamine metabolism

DOI:  https://doi.org/10.1016/j.celrep.2022.111234
Macromol Biosci. 2022 Aug 19. e2200248

Engineering the Surface Properties of DNA Nanostructures by Tuning the Valency of Assembling Species for Biomedical Applications.

Qian Liu, Jingruo Xia, Qingtao Yu, Pengcheng Gu, Yue Yuan, Ke Liu, Chaowang Huang, Chunfa Chen, Xiaolan Guo, Hang Qian.

  Self-assembled DNA nanostructures hold great potentials in biomedical applications. Nevertheless, the negatively charged DNA backbone and susceptivity to enzyme degradation pose challenges to this regard. Engineering the surface properties of DNA nanostructures by assembling DNA with guest molecules in magnesium-free system is promising to solve these issues. In this study, we investigated the polyamines-mediated DNA self-assembly with an emphasis on the valency of polyamines. Both spermine, spermidine, and putrescine can assemble DNA tetrahedron under appropriate concentrations. The cytotoxicity and cellular uptake efficiencies vary with the polyamine valency. Compared with magnesium-assembled DNA tetrahedron, polyamine-assembled DNA tetrahedron exhibited higher cellular uptake efficiency and serum stability. Circular dichroism spectrum results indicated that polyamines induce DNA conformation slightly shifting from B form to A form. The improved performances of polyamine-assembled DNA tetrahedrons under physiological settings are attributed to the surface properties that altered by guest molecules polyamine. The current study suggests that engineering the surface properties of DNA nanostructures by assembling them with guest cationic species is promising to further their biomedical applications. This article is protected by copyright. All rights reserved.

Keywords:  DNA nanostructures; magnesium-free assembly; noncanonical assembly; polyamines

DOI:  https://doi.org/10.1002/mabi.202200248
Exp Oncol. 2022 08;44(2): 148-154

POLYAMINES AS NEW POTENTIAL BIOMARKERS FOR DIFFERENTIAL DIAGNOSIS OF PROSTATE CANCER AND ESTIMATION OF ITS AGGRESSIVENESS.

S P Zaletok, O O Klenov, V V Bentrad, M P Prylutskyi, Yu V Vitruk, E O Stakhovsky, A V Timoshenko.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignancies in older men. The study of tissue markers of PCa can provide information about the state of proliferation and apoptosis in tumors, the susceptibility of tumor cells to metastasis and the mechanisms of resistance to therapy, which, in turn, can help predict the course of the disease and develop personalized treatment. Polyamines (PAs) spermine, spermidine, putrescine are of particular interest in terms of PCa tissue markers.
AIM: To investigate the levels of basic and acetylated forms of PAs in the postoperative samples of malignant and benign tumors of the human prostate and evaluate the possibility of their use for differential diagnosis and assessment of the PCa aggressiveness.
OBJECT AND METHODS: 57 postoperative tumor samples from patients with prostate adenocarcinoma of different Gleason score (GS) and clinical stage (T1-T4) and 20 samples of tumors from patients with benign prostate hyperplasia (BPH) were studied. The content of PAs was determined by high performance liquid chromatography.
RESULTS: Among the studied PAs, the most significant difference between PCa and BPH was observed for spermine (Spm). The level of Spm in PCa samples was 16 times lower than in BPH samples (p < 0.01). We did not find a significant dependence of PAs levels, including Spm, on the clinical stage. The association between the Spm level and the GS was established. The indolent (GS6) tumors were characterized by the highest Spm level while in the most aggressive (GS9 and GS10) tumors Spm content was the lowest.
CONCLUSIONS: A sharp decrease in Spm levels is probably a characteristic feature of prostate malignant tumors. The obtained results indicate an association of Spm levels in tumors with the GS. This may indicate Spm involvement in the formation of the aggressiveness of PCa. The results of the study can be further used for differential diagnosis of prostate tumors and for assessing the aggressiveness of PCa.
Nature. 2022 Aug 17.

LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages.

Zheng Wei, Joonseok Oh, Richard A Flavell, Jason M Crawford.

The mammalian immune system uses various pattern recognition receptors to recognize invaders and host damage and transmits this information to downstream immunometabolic signalling outcomes. Laccase domain-containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages and serves a central regulatory role in multiple inflammatory diseases such as inflammatory bowel diseases, arthritis and clearance of microbial infection1-4. However, the biochemical roles required for LACC1 functions remain largely undefined. Here we elucidated a shared biochemical function of LACC1 in mice and humans, converting L-citrulline to L-ornithine (L-Orn) and isocyanic acid and serving as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism. We validated the genetic and mechanistic connections among NOS2, LACC1 and ornithine decarboxylase 1 (ODC1) in mouse models and bone marrow-derived macrophages infected by Salmonella enterica Typhimurium. Strikingly, LACC1 phenotypes required upstream NOS2 and downstream ODC1, and Lacc1-/- chemical complementation with its product L-Orn significantly restored wild-type activities. Our findings illuminate a previously unidentified pathway in inflammatory macrophages, explain why its deficiency may contribute to human inflammatory diseases and suggest that L-Orn could serve as a nutraceutical to ameliorate LACC1-associated immunological dysfunctions such as arthritis or inflammatory bowel disease.

DOI: https://doi.org/10.1038/s41586-022-05111-3
Ann Rheum Dis. 2022 Aug 17. pii: annrheumdis-2022-222795. [Epub ahead of print]

Loss-of-function variants in SAT1 cause X-linked childhood-onset systemic lupus erythematosus.

Lingxiao Xu, Jian Zhao, Qing Sun, Xue Xu, Lei Wang, Ting Liu, Yunjuan Wu, Jingfeng Zhu, Linyu Geng, Yun Deng, Alexander Awgulewitsch, Diane L Kamen, Jim C Oates, Prithvi Raj, Edward K Wakeland, R Hal Scofield, Joel M Guthridge, Judith A James, Bevra H Hahn, Deborah K McCurdy, Fang Wang, Miaojia Zhang, Wenfeng Tan, Gary S Gilkeson, Betty P Tsao.

   OBJECTIVES: Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus.
METHODS: Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively.
RESULTS: The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African-American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1 p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte infiltration, proteinuria and elevated expression of type I interferon-inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3 +CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3 +CD4+ T cells correlated with decreased plasma levels of spermine in treatment-naive, incipient SLE patients.
CONCLUSIONS: We identified two novel SAT1 LOF variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identified SAT1 LOF variants as new monogenic causes for SLE.

Keywords:  Autoimmune Diseases; Immune System Diseases; Lupus Erythematosus, Systemic

DOI:  https://doi.org/10.1136/ard-2022-222795
Front Aging Neurosci. 2022 ;14 924984

Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study.

Jiahui Xu, Zhaoqing Sun, Rui Zhang, Ruixue Li, Zhecong Yu, Qianlong Zhang, Yanan Ma, Fuguo Xing, Liqiang Zheng.

   Background: Although animal studies show that spermidine (SPD) affects cognitive function, the relevant evidence among humans is limited. We aim to examine the association between serum SPD levels and cognitive performance.
Materials and Methods: We conducted a cross-sectional and longitudinal study including a baseline and one follow-up survey. The baseline survey was conducted from June 2019 to August 2019, while the follow-up survey was conducted from June 2021 to August 2021. We analyzed 3,774 adult participants aged >35 years, who had no history of dementia.
Results: The mean (SD) age of the participants was 57.4 (9.8) years. Relative to the first tertile, the multivariate-adjusted ORs (95% CIs) of mild cognitive impairment (MCI) for the second and third tertile groups were 0.78 (0.65, 0.93) and 0.80 (0.67, 0.96), respectively. Restricted cubic spline models show that there is a non-linear association between SPD and MCI. In line with cross-sectional findings, the longitudinal study showed that a high SPD concentration may indicate a lower risk of MCI [ORs (95% CIs) for the third tertile of 0.62 (0.39, 0.99)].
Conclusion: Our findings suggest that SPD is favorable for cognitive function. Monitoring the SPD levels may help reduce the incidence of MCI, hence decreasing the burden of MCI.

Keywords:  cognition; longitudinal study; mild cognitive impairment; rural; spermidine

DOI:  https://doi.org/10.3389/fnagi.2022.924984