CellPub Date : 2025-08-18DOI: 10.1016/j.cell.2025.07.043
Sven M Lange, Jeremy A Bennett, Robyn J Eisert, Alan Brown
{"title":"A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia.","authors":"Sven M Lange, Jeremy A Bennett, Robyn J Eisert, Alan Brown","doi":"10.1016/j.cell.2025.07.043","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.043","url":null,"abstract":"<p><p>The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. Defects in this process impair various signal-transduction pathways and cause ciliopathies. Although K63-linked ubiquitination appears to trigger protein export from cilia, the mechanisms coupling polyubiquitinated proteins to IFT remain unclear. Using a multidisciplinary approach, we demonstrate that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a GTPase involved in ciliary import, binds polyubiquitinated proteins and links them to retrograde IFT trains. CFAP36 uses a coincidence detection mechanism to simultaneously bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts hedgehog signaling, a pathway reliant on the retrieval of ubiquitinated receptors. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary homeostasis and demonstrate how structural changes in IFT trains achieve cargo selectivity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Conversion of IscB and Cas9 into RNA-guided RNA editors.","authors":"Chengtao Xu, Xiaolin Niu, Haifeng Sun, Hao Yan, Weixin Tang, Ailong Ke","doi":"10.1016/j.cell.2025.07.032","DOIUrl":"10.1016/j.cell.2025.07.032","url":null,"abstract":"<p><p>RNA-guided RNA editing represents an attractive alternative to DNA editing. However, the prevailing tool, CRISPR-Cas13, has collateral RNA cleavage activity that causes undesirable cytotoxicity in human cells. Here, we report an ultracompact RNA-editing platform engineered from IscB, which has comparable or higher activity than Cas13 but without cytotoxicity concerns. We show that IscB, the evolutionary ancestor of Cas9, has an intrinsic affinity for complementary single-stranded (ss)DNA and RNA. This activity becomes dominant when its double-stranded DNA binding activity is switched off through the deletion of its target-adjacent motif domain. The resulting R-IscB is comparable to or better than Cas13, can efficiently alter splicing outcomes in human cells, and can further mediate trans-splicing to correct any mutation at the mRNA level. R-IscB also drives efficient A-to-I editing on mRNA when fused to adenosine deaminase acting on RNA 2 (ADAR2) and mediates cleavage-based mRNA knockdown upon HNH engineering. Finally, we show that the same approach converts some Cas9s to RNA-targeting tools.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882288","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}
CellPub Date : 2025-08-15DOI: 10.1016/j.cell.2025.07.035
Daoming Chen, Zhou Yu, Wenbo Wu, Yingxue Du, Qianqian Du, Huanwei Huang, Yaqi Li, Ting Xuan, Ya-Chen Liang, Yang Liu, Zijuan Wang, Rina Su, Yi Zhao, Qi Li, Minmin Luo, Fengchao Wang, Ji Li, Cheng-Ming Chuong, Zhimiao Lin, Ting Chen
{"title":"Fibroblast bioelectric signaling drives hair growth","authors":"Daoming Chen, Zhou Yu, Wenbo Wu, Yingxue Du, Qianqian Du, Huanwei Huang, Yaqi Li, Ting Xuan, Ya-Chen Liang, Yang Liu, Zijuan Wang, Rina Su, Yi Zhao, Qi Li, Minmin Luo, Fengchao Wang, Ji Li, Cheng-Ming Chuong, Zhimiao Lin, Ting Chen","doi":"10.1016/j.cell.2025.07.035","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.035","url":null,"abstract":"Hair loss affects millions globally, significantly impacting quality of life and psychological well-being. Despite its prevalence, effective strategies for promoting human hair growth remain elusive. By investigating congenital generalized hypertrichosis terminalis (CGHT), a rare genetic disorder characterized by excessive hair growth, we discover that chromatin deletions or an inverted duplication disrupt the topologically associating domain (TAD), leading to the upregulation of the potassium channel <em>KCNJ2</em> in dermal fibroblasts. Mouse genetics demonstrate that KCNJ2-mediated membrane hyperpolarization in dermal fibroblasts promotes hair growth by enhancing fibroblasts Wnt signaling responses, involving a reduction in intracellular calcium levels. Notably, fibroblast membrane potential oscillates during the normal hair cycle, with hyperpolarization specifically associated with the growth phase. Inducing fibroblast membrane depolarization delays the growth phase, while KCNJ2-mediated hyperpolarization rescues hair loss in aging and androgenetic alopecia models. These results uncover a previously unrecognized role of fibroblast bioelectricity in tissue regeneration, offering novel therapeutic avenues for hair loss treatment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"24 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851404","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}
CellPub Date : 2025-08-15DOI: 10.1016/j.cell.2025.07.034
Nicholas W. Harper, Gavin A. Birdsall, Megan E. Honeywell, Kelly M. Ward, Athma A. Pai, Michael J. Lee
{"title":"RNA Pol II inhibition activates cell death independently from the loss of transcription","authors":"Nicholas W. Harper, Gavin A. Birdsall, Megan E. Honeywell, Kelly M. Ward, Athma A. Pai, Michael J. Lee","doi":"10.1016/j.cell.2025.07.034","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.034","url":null,"abstract":"RNA Pol II-mediated transcription is essential for eukaryotic life. Although loss of transcription is thought to be universally lethal, the associated mechanisms promoting cell death are not yet known. Here, we show that death following the loss of RNA Pol II activity does not result from dysregulated gene expression. Instead, it occurs in response to loss of the hypophosphorylated form of Rbp1 (also called RNA Pol IIA). Loss of RNA Pol IIA exclusively activates apoptosis, and expression of a transcriptionally inactive version of Rpb1 rescues cell viability. Using functional genomics, we identify the mechanisms driving lethality following the loss of RNA Pol IIA, which we call the Pol II degradation-dependent apoptotic response (PDAR). Using the genetic dependencies of PDAR, we identify clinically used drugs that owe their lethality to a PDAR-dependent mechanism. Our findings unveil an apoptotic signaling response that contributes to the efficacy of a wide array of anti-cancer therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"146 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851403","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}
CellPub Date : 2025-08-14DOI: 10.1016/j.cell.2025.06.015
Erin M. Kunz, Benyamin Abramovich Krasa, Foram Kamdar, Donald T. Avansino, Nick Hahn, Seonghyun Yoon, Akansha Singh, Samuel R. Nason-Tomaszewski, Nicholas S. Card, Justin J. Jude, Brandon G. Jacques, Payton H. Bechefsky, Carrina Iacobacci, Leigh R. Hochberg, Daniel B. Rubin, Ziv M. Williams, David M. Brandman, Sergey D. Stavisky, Nicholas AuYong, Chethan Pandarinath, Francis R. Willett
{"title":"Inner speech in motor cortex and implications for speech neuroprostheses","authors":"Erin M. Kunz, Benyamin Abramovich Krasa, Foram Kamdar, Donald T. Avansino, Nick Hahn, Seonghyun Yoon, Akansha Singh, Samuel R. Nason-Tomaszewski, Nicholas S. Card, Justin J. Jude, Brandon G. Jacques, Payton H. Bechefsky, Carrina Iacobacci, Leigh R. Hochberg, Daniel B. Rubin, Ziv M. Williams, David M. Brandman, Sergey D. Stavisky, Nicholas AuYong, Chethan Pandarinath, Francis R. Willett","doi":"10.1016/j.cell.2025.06.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.015","url":null,"abstract":"Speech brain-computer interfaces (BCIs) show promise in restoring communication to people with paralysis but have also prompted discussions regarding their potential to decode private inner speech. Separately, inner speech may be a way to bypass the current approach of requiring speech BCI users to physically attempt speech, which is fatiguing and can slow communication. Using multi-unit recordings from four participants, we found that inner speech is robustly represented in the motor cortex and that imagined sentences can be decoded in real time. The representation of inner speech was highly correlated with attempted speech, though we also identified a neural “motor-intent” dimension that differentiates the two. We investigated the possibility of decoding private inner speech and found that some aspects of free-form inner speech could be decoded during sequence recall and counting tasks. Finally, we demonstrate high-fidelity strategies that prevent speech BCIs from unintentionally decoding private inner speech.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"104 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840225","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":"Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy.","authors":"Zeguang Wu, Jinhong Shi, Qiezhong Lamao, Yuanyuan Qiu, Jinxin Yang, Yang Liu, Feifei Liang, Xue Sun, Wei Tang, Changya Chen, Qingming Yang, Chunmeng Wang, Zhifang Li, Haixia Zhang, Zhonghan Yang, Yunyi Zhang, Yuting Yi, Xufen Zheng, Yu Sun, Kuiying Ma, Lingling Yu, Huihui Yang, Zhaoxuan Wang, Wenjuan Zheng, Ling Yang, Zhixuan Zhang, Yongjian Zhang, Zhiqiang Wu, Yao Wang, Catherine C L Wong, Ming Jin, Pengfei Yuan, Weidong Han, Wensheng Wei","doi":"10.1016/j.cell.2025.07.046","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.046","url":null,"abstract":"<p><p>Despite the success of autologous chimeric antigen receptor (CAR)-T cell therapy, achieving persistence and avoiding rejection in allogeneic settings remains challenging. We showed that signal peptide peptidase-like 3 (SPPL3) deletion enabled glycan-mediated immune evasion in primary T cells. SPPL3 deletion modified glycan profiles on T cells, restricted ligand accessibility, and reduced allogeneic immunity without compromising the functionality of anti-CD19 CAR molecules. In a phase I clinical trial, SPPL3-null, T cell receptor (TCR)-deficient anti-CD19 allogeneic CAR-T cells reached the safety primary endpoint, with grade 3 or higher cytokine release syndrome (CRS) observed in 3 out of 9 patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) (ClinicalTrials.gov: NCT06014073). Reverse translational research highlighted the pivotal role of TCR in sustaining T cell persistence. We therefore evaluated the safety of SPPL3-null, TCR-sufficient CAR-T therapy on three patients with lymphoma or leukemia for compassionate care and observed no clinical signs of graft-versus-host disease. Our findings suggest glycan shielding by SPPL3 deletion is a promising direction for optimizing universal CAR-T therapies.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944190","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}
CellPub Date : 2025-08-14DOI: 10.1016/j.cell.2025.07.031
Jinlong Y. Lu, William B. Tu, Ronghui Li, Mingxi Weng, Bhargav D. Sanketi, Baolei Yuan, Pradeep Reddy, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
{"title":"Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming","authors":"Jinlong Y. Lu, William B. Tu, Ronghui Li, Mingxi Weng, Bhargav D. Sanketi, Baolei Yuan, Pradeep Reddy, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte","doi":"10.1016/j.cell.2025.07.031","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.031","url":null,"abstract":"The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a “mesenchymal drift” (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"292 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840129","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}
CellPub Date : 2025-08-14DOI: 10.1016/j.cell.2025.07.033
Aarti Krishnan, Melis N. Anahtar, Jacqueline A. Valeri, Wengong Jin, Nina M. Donghia, Leif Sieben, Andreas Luttens, Yu Zhang, Seyed Majed Modaresi, Andrew Hennes, Jenna Fromer, Parijat Bandyopadhyay, Jonathan C. Chen, Danyal Rehman, Ronak Desai, Paige Edwards, Ryan S. Lach, Marie-Stéphanie Aschtgen, Margaux Gaborieau, Massimiliano Gaetani, James J. Collins
{"title":"A generative deep learning approach to de novo antibiotic design","authors":"Aarti Krishnan, Melis N. Anahtar, Jacqueline A. Valeri, Wengong Jin, Nina M. Donghia, Leif Sieben, Andreas Luttens, Yu Zhang, Seyed Majed Modaresi, Andrew Hennes, Jenna Fromer, Parijat Bandyopadhyay, Jonathan C. Chen, Danyal Rehman, Ronak Desai, Paige Edwards, Ryan S. Lach, Marie-Stéphanie Aschtgen, Margaux Gaborieau, Massimiliano Gaetani, James J. Collins","doi":"10.1016/j.cell.2025.07.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.033","url":null,"abstract":"The antimicrobial resistance crisis necessitates structurally distinct antibiotics. While deep learning approaches can identify antibacterial compounds from existing libraries, structural novelty remains limited. Here, we developed a generative artificial intelligence framework for designing <em>de novo</em> antibiotics through two approaches: a fragment-based method to comprehensively screen >10<sup>7</sup> chemical fragments <em>in silico</em> against <em>Neisseria gonorrhoeae</em> or <em>Staphylococcus aureus</em>, subsequently expanding promising fragments, and an unconstrained <em>de novo</em> compound generation, each using genetic algorithms and variational autoencoders. Of 24 synthesized compounds, seven demonstrated selective antibacterial activity. Two lead compounds exhibited bactericidal efficacy against multidrug-resistant isolates with distinct mechanisms of action and reduced bacterial burden <em>in vivo</em> in mouse models of <em>N. gonorrhoeae</em> vaginal infection and methicillin-resistant <em>S. aureus</em> skin infection. We further validated structural analogs for both compound classes as antibacterial. Our approach enables the generative deep-learning-guided design of <em>de novo</em> antibiotics, providing a platform for mapping uncharted regions of chemical space.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"24 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840130","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}
CellPub Date : 2025-08-13DOI: 10.1016/j.cell.2025.07.038
Ryan Mahling, Bence Hegyi, Erin R Cullen, Timothy M Cho, Aaron R Rodriques, Lucile Fossier, Marc Yehya, Lin Yang, Bi-Xing Chen, Alexander N Katchman, Nourdine Chakouri, Ruiping Ji, Elaine Y Wan, Jared Kushner, Steven O Marx, Sergey Ovchinnikov, Christopher D Makinson, Donald M Bers, Manu Ben-Johny
{"title":"De novo design of a peptide modulator to reverse sodium channel dysfunction linked to cardiac arrhythmias and epilepsy.","authors":"Ryan Mahling, Bence Hegyi, Erin R Cullen, Timothy M Cho, Aaron R Rodriques, Lucile Fossier, Marc Yehya, Lin Yang, Bi-Xing Chen, Alexander N Katchman, Nourdine Chakouri, Ruiping Ji, Elaine Y Wan, Jared Kushner, Steven O Marx, Sergey Ovchinnikov, Christopher D Makinson, Donald M Bers, Manu Ben-Johny","doi":"10.1016/j.cell.2025.07.038","DOIUrl":"10.1016/j.cell.2025.07.038","url":null,"abstract":"<p><p>Ion channels orchestrate electrical signaling in excitable cells. In nature, ion channel function is customized by modulatory proteins that have evolved to fulfill distinct physiological needs. Yet, engineering synthetic modulators that precisely tune ion channel function is challenging. One example involves the voltage-gated sodium (Na<sub>V</sub>) channel that initiates the action potential and whose dysfunction amplifies the late/persistent sodium current (I<sub>NaL</sub>), a commonality that underlies various human diseases, including cardiac arrhythmias and epilepsy. Here, using a computational protein design platform, we engineered a de novo peptide modulator, engineered late-current inhibitor X by inactivation-gate release (ELIXIR), that binds Na<sub>V</sub> channels with submicromolar affinity. Functional analysis revealed unexpected selectivity in inhibiting \"pathogenic\" I<sub>NaL</sub> and confirmed its effectiveness in reversing Na<sub>V</sub> dysfunction linked to both cardiac arrhythmias and epilepsy in cellular and murine models. These findings exemplify the efficacy of de novo protein design for engineering synthetic ion channel modulators and set the stage for the rational design of future therapeutic approaches.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-13DOI: 10.1016/j.cell.2025.07.041
Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei
{"title":"Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.","authors":"Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei","doi":"10.1016/j.cell.2025.07.041","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.041","url":null,"abstract":"<p><p>RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N<sup>6</sup>-methyladenosine (m<sup>6</sup>A), N<sup>6</sup>,N<sup>6</sup>-dimethyladenosine (m<sup>6,6</sup>A), and N<sup>6</sup>-isopentenyladenosine (i<sup>6</sup>A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N<sup>6</sup>-modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m<sup>6</sup>A, m<sup>6,6</sup>A, and i<sup>6</sup>A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944209","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
