Pub Date : 2026-01-28DOI: 10.1016/j.cell.2025.12.029
Gabriella N.L. Chua, Emily C. Beckwitt, Victoria Miller-Browne, Olga Yurieva, Dan Zhang, Bryce J. Katch, Nina Y. Yao, John W. Watters, Kaitlin Abrantes, Ryogo Funabiki, Xiaolan Zhao, Michael E. O’Donnell, Shixin Liu
The ring-shaped sliding clamp proliferating cell nuclear antigen (PCNA) enables DNA polymerases to perform processive DNA synthesis during replication and repair. The loading of PCNA onto DNA is catalyzed by the ATPase clamp-loader replication factor C (RFC). Using a single-molecule platform to visualize the dynamic interplay between PCNA and RFC on DNA, we unexpectedly discovered that RFC continues to associate with PCNA after loading, contrary to the conventional view. Functionally, this clamp-loader/clamp (CLC) complex is required for processive DNA synthesis by polymerase ẟ (Polẟ), as the PCNA-Polẟ assembly is inherently unstable. This architectural role of RFC is dependent on the BRCA1 C-terminal homology (BRCT) domain of Rfc1, and mutation of its DNA-binding residues causes sensitivity to genotoxic stress in vivo. We further showed that flap endonuclease I (FEN1) can also stabilize the PCNA-Polẟ interaction and mediate robust synthesis. Overall, our work revealed that, beyond their canonical enzymatic functions, PCNA-binding proteins harbor non-catalytic functions important for DNA replication and genome maintenance.
环状滑动钳增殖细胞核抗原（PCNA）使DNA聚合酶在复制和修复过程中进行DNA合成。PCNA装载到DNA上是由atp酶夹装器复制因子C （RFC）催化的。利用单分子平台可视化DNA上PCNA和RFC之间的动态相互作用，我们意外地发现RFC在加载后继续与PCNA结合，这与传统观点相反。在功能上，这种夹夹加载器/夹夹（CLC）复合体是聚合酶ẟ （Polẟ）进行DNA合成所必需的，因为PCNA-Polẟ组装本身是不稳定的。RFC的这种结构作用依赖于RFC的BRCA1 c -末端同源性（BRCT）结构域，其dna结合残基的突变导致体内对基因毒性应激的敏感性。我们进一步发现皮瓣内切酶I （FEN1）也可以稳定PCNA-Polẟ相互作用并介导稳健的合成。总的来说，我们的工作表明，除了它们典型的酶功能外，pcna结合蛋白还具有对DNA复制和基因组维持重要的非催化功能。
{"title":"A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis","authors":"Gabriella N.L. Chua, Emily C. Beckwitt, Victoria Miller-Browne, Olga Yurieva, Dan Zhang, Bryce J. Katch, Nina Y. Yao, John W. Watters, Kaitlin Abrantes, Ryogo Funabiki, Xiaolan Zhao, Michael E. O’Donnell, Shixin Liu","doi":"10.1016/j.cell.2025.12.029","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.029","url":null,"abstract":"The ring-shaped sliding clamp proliferating cell nuclear antigen (PCNA) enables DNA polymerases to perform processive DNA synthesis during replication and repair. The loading of PCNA onto DNA is catalyzed by the ATPase clamp-loader replication factor C (RFC). Using a single-molecule platform to visualize the dynamic interplay between PCNA and RFC on DNA, we unexpectedly discovered that RFC continues to associate with PCNA after loading, contrary to the conventional view. Functionally, this clamp-loader/clamp (CLC) complex is required for processive DNA synthesis by polymerase ẟ (Polẟ), as the PCNA-Polẟ assembly is inherently unstable. This architectural role of RFC is dependent on the BRCA1 C-terminal homology (BRCT) domain of Rfc1, and mutation of its DNA-binding residues causes sensitivity to genotoxic stress <em>in vivo</em>. We further showed that flap endonuclease I (FEN1) can also stabilize the PCNA-Polẟ interaction and mediate robust synthesis. Overall, our work revealed that, beyond their canonical enzymatic functions, PCNA-binding proteins harbor non-catalytic functions important for DNA replication and genome maintenance.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"78 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070585","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}
Pub Date : 2026-01-24DOI: 10.1016/j.cell.2026.01.004
Shu-Ting Hung, Gabriel R. Linares, Wen-Hsuan Chang, Yunsun Eoh, Gopinath Krishnan, Stacee Mendonca, Sarah Hong, Yingxiao Shi, Manuel Santana, Chuol Kueth, Samantha Macklin-Isquierdo, Sarah Perry, Sarah Duhaime, Claudia Maios, Jonathan Chang, Joscany Perez, Alexander Couto, Jesse Lai, Yichen Li, Samuel V. Alworth, Justin K. Ichida
(Cell 186, 786–802.e1–e15; February 16, 2023)
（Cell 186, 786-802.e1-e15； 2023年2月16日）
{"title":"PIKFYVE inhibition mitigates disease in models of diverse forms of ALS","authors":"Shu-Ting Hung, Gabriel R. Linares, Wen-Hsuan Chang, Yunsun Eoh, Gopinath Krishnan, Stacee Mendonca, Sarah Hong, Yingxiao Shi, Manuel Santana, Chuol Kueth, Samantha Macklin-Isquierdo, Sarah Perry, Sarah Duhaime, Claudia Maios, Jonathan Chang, Joscany Perez, Alexander Couto, Jesse Lai, Yichen Li, Samuel V. Alworth, Justin K. Ichida","doi":"10.1016/j.cell.2026.01.004","DOIUrl":"https://doi.org/10.1016/j.cell.2026.01.004","url":null,"abstract":"(Cell <em>186</em>, 786–802.e1–e15; February 16, 2023)","PeriodicalId":9656,"journal":{"name":"Cell","volume":"51 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146042952","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}
Pub Date : 2026-01-23DOI: 10.1016/j.cell.2025.12.033
Jonathan E. Pekar, Alvin Crespo-Bellido, Philippe Lemey, Andrew S. Bowman, Thomas P. Peacock, Jennine N. Ochoa, Andrew Rambaut, Oliver G. Pybus, Michael Worobey, Martha I. Nelson
{"title":"Can H5N1 avian influenza in dairy cattle be contained in the US?","authors":"Jonathan E. Pekar, Alvin Crespo-Bellido, Philippe Lemey, Andrew S. Bowman, Thomas P. Peacock, Jennine N. Ochoa, Andrew Rambaut, Oliver G. Pybus, Michael Worobey, Martha I. Nelson","doi":"10.1016/j.cell.2025.12.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.033","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"119 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033203","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}
Pub Date : 2026-01-22Epub Date: 2025-12-29DOI: 10.1016/j.cell.2025.11.041
Zishuo Yu, Pradeep Sathyanarayana, Cong Liu, Joel M J Tan, Pan Yang, Biswajit Das, Side Hu, Xiaoyi Fan, Chenggong Ji, Sandra K Weller, Mrinal Shekhar, Donald M Coen, Philip J Kranzusch, Joseph J Loparo, Jonathan Abraham
Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.
{"title":"Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly.","authors":"Zishuo Yu, Pradeep Sathyanarayana, Cong Liu, Joel M J Tan, Pan Yang, Biswajit Das, Side Hu, Xiaoyi Fan, Chenggong Ji, Sandra K Weller, Mrinal Shekhar, Donald M Coen, Philip J Kranzusch, Joseph J Loparo, Jonathan Abraham","doi":"10.1016/j.cell.2025.11.041","DOIUrl":"10.1016/j.cell.2025.11.041","url":null,"abstract":"<p><p>Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"478-494.e18"},"PeriodicalIF":42.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862341","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}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.006
Alejandro De Los Angeles, Tim Bayne, Nissim Benvenisty, Hongkui Deng, Misao Fujita, Weizhi Ji, Stephen Latham, Tianqing Li, Pentao Liu, Yuin-Han Loh, Jeantine Lunshof, Duanqing Pei, Nam Pho, José C.R. Silva, Timothy Theodore Ka Ki Tam, Tan Tao, Alan Trounson, Shao Xu, Leqian Yu, Julian Koplin, Alan Regenberg, Kiminobu Sugaya, Julian Savulescu, Magdalena Zernicka-Goetz, Robin Lovell-Badge
{"title":"A two-tier framework for responsible research on human embryo models","authors":"Alejandro De Los Angeles, Tim Bayne, Nissim Benvenisty, Hongkui Deng, Misao Fujita, Weizhi Ji, Stephen Latham, Tianqing Li, Pentao Liu, Yuin-Han Loh, Jeantine Lunshof, Duanqing Pei, Nam Pho, José C.R. Silva, Timothy Theodore Ka Ki Tam, Tan Tao, Alan Trounson, Shao Xu, Leqian Yu, Julian Koplin, Alan Regenberg, Kiminobu Sugaya, Julian Savulescu, Magdalena Zernicka-Goetz, Robin Lovell-Badge","doi":"10.1016/j.cell.2025.12.006","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.006","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"95 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033204","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}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.014
Michelle F. Griffin, Dayan J. Li, Kellen Chen, Jennifer B.L. Parker, Jason L. Guo, Seungsoo Kim, Katerina Kraft, Mauricio Downer, Annah G. Morgan, Maxwell M. Kuhnert, Serena L. Jing, Hanqi Yao, Caleb Valencia, Asha Cotterell, Michael Januszyk, Geoffrey C. Gurtner, Howard Y. Chang, Joanna Wysocka, Derrick C. Wan, Michael T. Longaker
{"title":"Fibroblasts of disparate developmental origins harbor anatomically variant scarring potential","authors":"Michelle F. Griffin, Dayan J. Li, Kellen Chen, Jennifer B.L. Parker, Jason L. Guo, Seungsoo Kim, Katerina Kraft, Mauricio Downer, Annah G. Morgan, Maxwell M. Kuhnert, Serena L. Jing, Hanqi Yao, Caleb Valencia, Asha Cotterell, Michael Januszyk, Geoffrey C. Gurtner, Howard Y. Chang, Joanna Wysocka, Derrick C. Wan, Michael T. Longaker","doi":"10.1016/j.cell.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.014","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033205","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}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.019
Leonie Uhl, Amel Aziba, Sinah Löbbert, Timothy Russell, Bastian Krenz, Francisco Montesinos, Toshitha Kannan, Omkar R. Valanju, Christina Schülein-Völk, Tim de Martines, Michael Bolz, Daniel Fleischhauer, Giacomo Cossa, Theresa Endres, Daniel Solvie, Peter Gallant, Andreas Rosenwald, Hans M. Maric, Dimitrios Papadopoulos, Seychelle M. Vos, Martin Eilers
{"title":"MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids","authors":"Leonie Uhl, Amel Aziba, Sinah Löbbert, Timothy Russell, Bastian Krenz, Francisco Montesinos, Toshitha Kannan, Omkar R. Valanju, Christina Schülein-Völk, Tim de Martines, Michael Bolz, Daniel Fleischhauer, Giacomo Cossa, Theresa Endres, Daniel Solvie, Peter Gallant, Andreas Rosenwald, Hans M. Maric, Dimitrios Papadopoulos, Seychelle M. Vos, Martin Eilers","doi":"10.1016/j.cell.2025.12.019","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.019","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"283 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033910","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}
Pub Date : 2026-01-22Epub Date: 2025-12-22DOI: 10.1016/j.cell.2025.11.031
Constantine N Tzouanas, Jessica E S Shay, Marc S Sherman, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Junyan Tao, Brandon M Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P Monga, Georg M Lauer, Wolfram Goessling, Ömer H Yilmaz, Alex K Shalek
During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress' functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells' early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.
{"title":"Hepatic adaptation to chronic metabolic stress primes tumorigenesis.","authors":"Constantine N Tzouanas, Jessica E S Shay, Marc S Sherman, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Junyan Tao, Brandon M Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P Monga, Georg M Lauer, Wolfram Goessling, Ömer H Yilmaz, Alex K Shalek","doi":"10.1016/j.cell.2025.11.031","DOIUrl":"10.1016/j.cell.2025.11.031","url":null,"abstract":"<p><p>During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress' functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells' early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"435-460.e28"},"PeriodicalIF":42.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818157","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}
Pub Date : 2026-01-22DOI: 10.1016/j.cell.2025.12.012
Ali Ghoochani, Julia C. Heiby, Eshaan S. Rawat, Uche N. Medoh, Domenico Di Fraia, Wentao Dong, Marc Gastou, Mohit Rastogi, Vincent Hernandez, Kwamina Nyame, Nouf N. Laqtom, William Durso, Christina Valkova, Alina Isakova, Christoph Kaether, Marius Wernig, Natalia Gomez-Ospina, Christian Franke, Alessandro Ori, Monther Abu-Remaileh
Mutations in lysosomal genes cause neurodegeneration and neuronopathic lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of lysosomes from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of proteins not previously annotated as lysosomal and reveal the diversity of lysosomal composition across brain cell types. Notably, we identified SLC45A1, a gene whose mutations cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. SLC45A1 functions as a lysosomal sugar transporter and impacts the stability of the V1 subunits of the vacuolar ATPase (V-ATPase). Consistently, SLC45A1 loss reduces lysosomal V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis, causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as an LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution.
{"title":"Cell-type resolved protein atlas of brain lysosomes identifies SLC45A1-associated disease as a lysosomal disorder","authors":"Ali Ghoochani, Julia C. Heiby, Eshaan S. Rawat, Uche N. Medoh, Domenico Di Fraia, Wentao Dong, Marc Gastou, Mohit Rastogi, Vincent Hernandez, Kwamina Nyame, Nouf N. Laqtom, William Durso, Christina Valkova, Alina Isakova, Christoph Kaether, Marius Wernig, Natalia Gomez-Ospina, Christian Franke, Alessandro Ori, Monther Abu-Remaileh","doi":"10.1016/j.cell.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.012","url":null,"abstract":"Mutations in lysosomal genes cause neurodegeneration and neuronopathic lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of lysosomes from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of proteins not previously annotated as lysosomal and reveal the diversity of lysosomal composition across brain cell types. Notably, we identified SLC45A1, a gene whose mutations cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction <em>in vitro</em> and <em>in vivo</em>. SLC45A1 functions as a lysosomal sugar transporter and impacts the stability of the V1 subunits of the vacuolar ATPase (V-ATPase). Consistently, SLC45A1 loss reduces lysosomal V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis, causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as an LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"195 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022175","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}
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