September 13, 2019 Science journal essence

September 29, 2019 / BIOON / - -- a new issue of Science Journal (September 13, 2019) will be published this week What are the highlights of its research? Let Xiaobian come together The picture is from science journal 1 Science: the research team of Cao Xuetao in China revealed that the mechanism of m6A mediated cell metabolism reprogramming inhibition of virus infection doi: 10.1126/science.aax4468 virus infection can regulate the metabolism of host cells, thus affecting the survival or clearance of the virus RNA modification, especially the most common mammalian mRNA modification, N6-methyladenosine (m6A), can regulate gene expression and virus infection For example, mettl3 / 14, a component of m6A methyltransferase complex, restricts the production of Zika virus, while alkbh5 and FTO, m6A demethylase, enhance the production of Zika virus In the interaction between virus and host, the reprogramming of cell metabolism mediated by m6A modification is not clear In a new study, researchers from Peking Union Medical College, Nankai University, West Lake University, Basic Medical Research Institute of Chinese Academy of Medical Sciences and the Second Military Medical University measured the level of m6A in host cells infected with the virus in order to explore the role of mRNA modified m6A in the response of hosts to virus infection During the infection period of VSV (vesicular stomatitis virus) in primary peritoneal macrophages of mice, the level of m6A in total RNA first increased, then decreased, and with the increase of viral load and then decreased They then conducted RNAi mediated functional screening of m6A methyltransferase complex (mettl3, mettl14 and wtap) and m6A demethylase (alkbh5 and FTO), and found that knockdown of alkbh5 reduced VSV RNA level to the greatest extent, which was then verified by four independent siRNAs When infected with a VSV expressing recombinant GFP (gfp-vsv), the knockout of alkbh5 by crispr-cas9 in mouse macrophage RAW264.7 also reduced the production of intracellular virus The related research results were published in the Science Journal on September 13, 2019, and the paper title is "N6 metadata RNA modification – mediated cell metadata rewiring in hibits virtual replication" The corresponding author is academician Xuetao Cao They confirmed that nine major metabolic related genes were significantly down-regulated or up-regulated in macrophages lacking alkbh5 after viral infection Among these genes, ogdh (encoding α - ketoglutarate dehydrogenase) is the most significantly down regulated gene Lack of alkbh5 or virus inhibition could significantly down regulate the expression of ogdh The expression of ogdh was also down regulated in different types of RNA or DNA viruses, but the response to TLR ligand stimulation remained unchanged Furthermore, it has been previously reported that ogdh expression is inhibited after human pandemic virus infection The functional screening of these nine metabolism related genes showed that ogdh knockdown was the most powerful inhibitor of virus replication, accompanied by decreased IFN - β expression and lack of phenotype simulation of alkbh5 Besides scgb1a1 knockdown, the inhibition effect of other metabolic genes knockdown was not as good as ogdh knockdown Other candidate genes not involved in TCA cycle did not cross regulate with ogdh in this process In addition, ogdh knockdown reduced viral replication and IFN-I expression in human THP-1 cells Therefore, the inhibition of the expression of ogdh is a universal mechanism for the inhibition of virus in host cells Targeted metabonomics analysis showed that ogdh silencing changed the levels of several important metabolites in macrophages infected by virus One of the metabolic intermediates in this decline is aspartic acid, which is known to promote viral replication, consistent with the previously reported depletion of aspartic acid by ogdh silencing Itaconate is one of the most significantly down regulated metabolites in macrophages with ogdh silenced after virus infection Itaconic acid was transformed from CIS aconitate, one of the intermediate products of TCA cycle, and its level in macrophages silenced by ogdh also decreased As the most abundant metabolite in lipopolysaccharide treated macrophages, itaconic acid plays an anti-inflammatory role by regulating mitochondrial respiration and metabolic remodeling or activating Nrf2 through Keap1 alkylation However, the role of itaconic acid in regulating viral replication is still unknown Treatment of macrophages lacking alkbh5 with dimethyl itaconate (DMI), a cell permeable itaconate derivative, can save virus replication in a dose-dependent manner Another cell permeable derivative of itaconic acid, 4-octyl itaconate, can effectively save the replication of the virus Itaconic acid 4-octyl ester also saved viral replication in macrophages silenced by ogdh and promoted viral replication in a dose-dependent manner Finally, in this new study, these researchers elucidated that host cells actively respond to viral infection by weakening the demethylation activity of alkbh5, which will lead to increased ogdh mRNA decay and decreased ogdh protein expression, thus reprogramming the metabolic state of cells and making the host produce IFN-I independent resistance to viral infection Decreased ogdh expression limits the tricarboxylic acid cycle and reduces the production of itaconic acid required for viral replication, thus limiting viral infection in host cells They believe that the conversation between m6A RNA modification and metabolizing reprogramming via the alkbh5-ogdh-itaconic acid pathway provides new insights into the mechanism of cell resistance to invasive pathogens through metabolizing reprogramming that is not related to innate responses Identification of cell metabolites in host-virus interactions helps to better understand the process of virus infection and to identify potential targets for intervention This new study shows that ogdh and itaconic acid promote virus replication in a way independent of innate immune response, and proposes to control viral infectious diseases by targeting the metabolic response of ogdh itaconic acid 2 Science: to reveal the mitochondrial ribosome assembly pathway doi: 10.1126/science.aaw5570; doi: 10.1126/science.aay7771 ribosome biogenesis is a multi-step process promoted by assembly factors Saurer et al Provided structural information on the maturation of mitochondrial ribosomes in Trypanosoma brucei Cells have evolved a specific mechanism for the maturation of mitochondrial ribosome subunits, including the formation of three distinct and well structured assembly intermediates The comparison between these assembly intermediates and mature mitochondrial ribosomes shows how assembly factors and ribosomal proteins work together to fold and stabilize ribosomal RNA 3 Science: the structure reveals that the capture and transport cycle of P4 ATPase, DOI: 10.1126/science.aay3353 eukaryotic cell membrane has different lipid composition in its inner and outer lobules The enzyme flippase (a turnover enzyme, which refers to turning the lipid end of the molecule from the outer membrane side to the inner membrane side) and floppase (a turnover enzyme, which turns the lipid end of the molecule from the inner membrane side to the outer membrane side) respectively use the energy generated by ATP hydrolysis to transport lipids according to the concentration gradient from the outer leaflet to the inner leaflet or from the inner leaflet to the outer leaflet Flippase is a P4 ATPase, which plays an important role in membrane transport, signal transduction and apoptosis Hiraizumi et al Reported the low-temperature electron microscopic structure of six intermediates when human flippase atp8a1 is combined with its chaperone CDC50, which is required for its function ATP binding and autophosphorylation in atp8a1 drive a conformational cycle in which lipids bind in different ways, thus facilitating translocation 4 Science: new nicotine insecticides reduce fat storage of songbirds and delay their migration doi: 10.1126/science.aaw9419 new nicotine insecticides (neonicotinoids) are widely used insecticides They have been found to have a negative impact on an increasing number of species, especially pollinators Eng et al Tested how exposure to these compounds affected the behavior of migratory songbirds The intake of new nicotine insecticides at the actual level in the field reduced the accumulation of food intake and body weight, as well as fat storage, leading to a delay in leaving the stopover site This delay may lead to a decline in migration survival and reproductive success, and therefore may have an impact on songbird populations 5 Science: explore the relationship between hide and seek behavior and nerve in rats doi: 10.1126/science.aax4705 there may be controversy about the universality and evolutionary function of animal game behavior Reinhold et al confirmed that rats can play hide and seek with humans In the "seek" state, rats learn to look for hidden humans and keep looking until they find them In the "hide" state, they learn to hide in one of several locations and wait until they are found In both cases, rats were rewarded for social interaction with humans Rats make sounds when they are searching and discovering, and remain silent when they are hiding The recording in medial prefrontal cortex detected neurons sensitive to game structure (BIOON Com)