bims-polyam 2021-06-27 papers

Nat Commun. 2021 Jun 25. 12(1): 3973

Structure and transport mechanism of P5B-ATPases.

Ping Li, Kaituo Wang, Nina Salustros, Christina Grønberg, Pontus Gourdon.

In human cells, P5B-ATPases execute the active export of physiologically important polyamines such as spermine from lysosomes to the cytosol, a function linked to a palette of disorders. Yet, the overall shape of P5B-ATPases and the mechanisms of polyamine recognition, uptake and transport remain elusive. Here we describe a series of cryo-electron microscopy structures of a yeast homolog of human ATP13A2-5, Ypk9, determined at resolutions reaching 3.4 Å, and depicting three separate transport cycle intermediates, including spermine-bound conformations. Surprisingly, in the absence of cargo, Ypk9 rests in a phosphorylated conformation auto-inhibited by the N-terminus. Spermine uptake is accomplished through an electronegative cleft lined by transmembrane segments 2, 4 and 6. Despite the dramatically different nature of the transported cargo, these findings pinpoint shared principles of transport and regulation among the evolutionary related P4-, P5A- and P5B-ATPases. The data also provide a framework for analysis of associated maladies, such as Parkinson's disease.

DOI: https://doi.org/10.1038/s41467-021-24148-y

Nat Commun. 2021 06 21. 12(1): 3818

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals.

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.

DOI: https://doi.org/10.1038/s41467-021-24007-w

DNA Cell Biol. 2021 Jun 24.

Ectopic Expression of GhSAMDC3 Enhanced Salt Tolerance Due to Accumulated Spd Content and Activation of Salt Tolerance-Related Genes in Arabidopsis thaliana.

Xinxin Tang, Lan Wu, Fanlong Wang, Wengang Tian, Xiaoming Hu, Shuangxia Jin, Huaguo Zhu.

Polyamines (PAs), especially spermidine and spermine (which are involved in various types of abiotic stress tolerance), have been reported in many plant species. In this study, we identified 14 putative S-adenosylmethionine decarboxylase genes (GhSAMDC1-14) in upland cotton. Based on phylogenetic and expression analyses conducted under different abiotic stresses, we selected and transferred GhSAMDC3 into Arabidopsis thaliana. Compared to the wild type, transgenic plants displayed rapid growth and increases in average leaf area and leaf number of 52% and 36%, respectively. In transgenic plants, the germination vigor and rate were markedly enhanced under NaCl treatment, and the plant survival rate increased by 50% under 300 mM NaCl treatment. The spermidine content was significantly increased, possibly due to the synthesis of a series of PAs and oxidant and antioxidant genes, resulting in improved salinity tolerance in Arabidopsis. Various salinity resistance-related genes were upregulated in transgenic plants. Together, these results indicate that ectopic expression of GhSAMDC3 raised salinity tolerance by the accumulation of spermidine and activation of salinity tolerance-related genes in A. thaliana.

Keywords: Arabidopsis thaliana; GhSAMDC3; polyamines; salinity tolerance

DOI: https://doi.org/10.1089/dna.2020.6064