{"title":"Ketone signaling goes nuclear","authors":"Jose L. Nieto-Torres, Enric Mocholi Gimeno","doi":"10.1038/s41589-026-02321-y","DOIUrl":"10.1038/s41589-026-02321-y","url":null,"abstract":"The nucleus is increasingly recognized as a metabolically active hub. A study shows how the ketolytic enzyme OXCT1 translocates to the nucleus to locally deplete β-hydroxybutyrate, suppressing anti-tumor immunity through site-specific epigenetic remodeling.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 10","pages":"1561-1562"},"PeriodicalIF":15.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jingjing Sun, Junzhou Wu, Yifeng Yuan, Seetharamsing Balamkundu, Agnieszka Dziergowska, Hazel Chay Suen Suen, Dwijapriya, Cui Liang, Léo Hardy, Megan En Lee, Grazyna Leszczynska, Chuan-Fa Liu, Zeynep Baharoglu, Laurence Drouard, Steven D Bruner, Thomas J Begley, Valérie de Crécy-Lagard, Peter C Dedon
{"title":"Pyridoxal-phosphate-dependent biosynthesis of aminovaleramide by AvaS in tRNA.","authors":"Jingjing Sun, Junzhou Wu, Yifeng Yuan, Seetharamsing Balamkundu, Agnieszka Dziergowska, Hazel Chay Suen Suen, Dwijapriya, Cui Liang, Léo Hardy, Megan En Lee, Grazyna Leszczynska, Chuan-Fa Liu, Zeynep Baharoglu, Laurence Drouard, Steven D Bruner, Thomas J Begley, Valérie de Crécy-Lagard, Peter C Dedon","doi":"10.1038/s41589-026-02303-0","DOIUrl":"https://doi.org/10.1038/s41589-026-02303-0","url":null,"abstract":"<p><p>In eubacteria, decoding of isoleucine codon AUA requires a specialized tRNA (tRNA<sup>Ile2</sup>) modified with lysidine (k<sup>2</sup>C) at the anticodon wobble position (C<sub>34</sub>), which switches decoding specificity from methionine (AUG) to isoleucine (AUA). Recently, aminovaleramide cytidine (ava<sup>2</sup>C) was discovered at the same tRNA position in several bacteria and plants and shown to support AUA decoding and Ile-specific aminoacylation. However, the enzyme catalyzing ava<sup>2</sup>C was unknown. Here, we report that tRNA<sup>Ile</sup>-aminovaleramididine synthetase (AvaS) catalyzes ava<sup>2</sup>C biosynthesis in Pseudomonas aeruginosa PA14. AvaS converts k<sup>2</sup>C to ava<sup>2</sup>C through a pyridoxal-phosphate-dependent oxidative decarboxylation mechanism, supported by site-directed mutagenesis and in vitro enzymatic assays. Dual-reporter assays demonstrated that ava<sup>2</sup>C-modified tRNA exhibits lower AUA decoding efficiency than k<sup>2</sup>C-modified tRNA. Additionally, genome-wide screening revealed an unexpected link between ava<sup>2</sup>C levels and metabolic and stress response pathways influencing i<sup>6</sup>A/ms<sup>2</sup>i<sup>6</sup>A dynamics. Together, these findings define the molecular basis of ava<sup>2</sup>C biosynthesis and its broader cellular metabolic networks.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luca A Andronico, Cenk O Gurdap, Abishek Arora, Franziska Ragaller, Patrick A Sandoz, Yidan Jiang, Sarantis Giatrellis, Leonard L de Boer, Valentina Carannante, Sofiia Iskrak, Jaromir Mikes, Marcus Buggert, Anders Österborg, Björn Önfelt, Andrey S Klymchenko, Petter Brodin, Erdinc Sezgin
{"title":"Plasma membrane order maps functional diversity in immune cells.","authors":"Luca A Andronico, Cenk O Gurdap, Abishek Arora, Franziska Ragaller, Patrick A Sandoz, Yidan Jiang, Sarantis Giatrellis, Leonard L de Boer, Valentina Carannante, Sofiia Iskrak, Jaromir Mikes, Marcus Buggert, Anders Österborg, Björn Önfelt, Andrey S Klymchenko, Petter Brodin, Erdinc Sezgin","doi":"10.1038/s41589-026-02322-x","DOIUrl":"https://doi.org/10.1038/s41589-026-02322-x","url":null,"abstract":"<p><p>Cell membranes undergo biophysical remodeling as an adaptation to the surroundings and to perform specific biological functions. However, the extent and relevance of such changes in human immune cells remain unknown, largely because of the lack of single-cell and multidimensional methodologies. Here we apply a cytometry-based method to fill this gap by combining biophysical profiling with simultaneous analysis of immune cell markers. This platform reveals notable cell-type-dependent plasma membrane order heterogeneity in immune cells. By sorting immune cells according to their membrane order and performing transcriptome and spatial surface proteome analyses together with functional tests, we show that plasma membrane order can be used to identify subsets of immune cells with distinct phenotypes and functional behaviors. Our findings demonstrate a broad heterogeneity of plasma membrane order in immune cells that will provide a more precise definition of immune cell states on the basis of their biophysical properties in health and disease.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samer Saleh, Ning-Hsiang Hsu, Emma Luu, Vincent C Martin, Hans Jefferson C Ng, William B Black, Shiding Zhang, Jin-Kwang Kim, Banumathi Sankaran, Andre H T Tran, Ryan L Hayes, Justin B Siegel, Feng Qiao, Han Li
{"title":"A sequence motif enables widespread use of noncanonical redox cofactors in natural enzymes.","authors":"Samer Saleh, Ning-Hsiang Hsu, Emma Luu, Vincent C Martin, Hans Jefferson C Ng, William B Black, Shiding Zhang, Jin-Kwang Kim, Banumathi Sankaran, Andre H T Tran, Ryan L Hayes, Justin B Siegel, Feng Qiao, Han Li","doi":"10.1038/s41589-026-02315-w","DOIUrl":"10.1038/s41589-026-02315-w","url":null,"abstract":"<p><p>Noncanonical redox cofactors (NRCs) are low-cost alternatives to the natural redox cofactors nicotinamide adenine dinucleotide (NAD<sup>+</sup>) and nicotinamide adenine dinucleotide phosphate (NADP<sup>+</sup>) for biomanufacturing, offering exquisite electron-delivery control, yet their adoption is limited by the scarcity of compatible enzymes. Screening the aldehyde dehydrogenase (ALDH) family, we identified a conserved RH/QxxR motif that enables widespread NRC activity among natural enzymes. Bos taurus ALDH3a1 exhibits unprecedented turnover with nicotinamide mononucleotide (NMN<sup>+</sup>), with k<sub>cat</sub> values exceeding NAD<sup>+</sup> and surpassing most engineered NRC-active enzymes by 10-10<sup>5</sup>-fold. Structural analyses reveal that this motif reinforces cofactor positioning and preorganizes the active site independently of the NAD<sup>+</sup> adenosine monophosphate moiety. This motif supports activity across simple-synthetic NRCs such as 1-(2-carbamoylmethyl)nicotinamide and, when introduced into diverse ALDH scaffolds, enhances NMN<sup>+</sup> activity up to 60-fold. These findings elucidate nature's solution to engineering NRC-active enzymes and offer a blueprint to mine latent evolutionary plasticity in natural enzymes that serve as superior engineering starting points.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Macrophages are what they eat.","authors":"Jacob Geri","doi":"10.1038/s41589-026-02311-0","DOIUrl":"https://doi.org/10.1038/s41589-026-02311-0","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regan F Volk, Amy C Fan, Sara W Casebeer, Vishnu R Tejus, Andrew C Condon, Bahar Zirak, Nayelis A Manon, Iryna Irkliyenko, Danielle M Torralba, Shao Tao, Tommaso Pollini, Vijay Ramani, Ajay V Maker, Matthew F Krummel, Hani Goodarzi, Balyn W Zaro
{"title":"Macrophages transfer functional proteins to their surface during live-cell uptake.","authors":"Regan F Volk, Amy C Fan, Sara W Casebeer, Vishnu R Tejus, Andrew C Condon, Bahar Zirak, Nayelis A Manon, Iryna Irkliyenko, Danielle M Torralba, Shao Tao, Tommaso Pollini, Vijay Ramani, Ajay V Maker, Matthew F Krummel, Hani Goodarzi, Balyn W Zaro","doi":"10.1038/s41589-026-02292-0","DOIUrl":"https://doi.org/10.1038/s41589-026-02292-0","url":null,"abstract":"<p><p>A cell's proteome is assumed to reflect its transcriptional and translational activity. Macrophages regularly acquire xenobiotic material from neighboring cells, which is thought to result in degradation of the material. However, increasing lines of evidence suggest that not all taken up material is degraded and other transfer-like processes also occur. Field standard technologies are unable to rigorously report on precisely how and by whom the macrophage protein repertoire is altered during these interactions, leaving unresolved the extent to which nondegradative processes contribute to altered phenotypes. Here, we leveraged chemical tools and proteomics to show that intact target cancer cell surface proteins are transferred to the macrophage cell surface at functionally impactful levels in a manner associated with live-cell uptake. Widespread acquisition of proteins during cell uptake reengineers the macrophage cell surface proteome and is a transcriptionally silent, cell-nonautonomous process with the potential to alter metabolic uptake.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}