EMBO Reports最新文献_第7页

The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation. 溶酶体应激和损伤反应的范围：从机械传感到炎症。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-27 DOI: 10.1038/s44319-025-00405-9

Ori Scott, Ekambir Saran, Spencer A Freeman

{"title":"The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.","authors":"Ori Scott, Ekambir Saran, Spencer A Freeman","doi":"10.1038/s44319-025-00405-9","DOIUrl":"10.1038/s44319-025-00405-9","url":null,"abstract":"Cells and tissues turn over their aged and damaged components in order to adapt to a changing environment and maintain homeostasis. These functions rely on lysosomes, dynamic and heterogeneous organelles that play essential roles in nutrient redistribution, metabolism, signaling, gene regulation, plasma membrane repair, and immunity. Because of metabolic fluctuations and pathogenic threats, lysosomes must adapt in the short and long term to maintain functionality. In response to such challenges, lysosomes deploy a variety of mechanisms that prevent the breaching of their membrane and escape of their contents, including pathogen-associated molecules and hydrolases. While transient permeabilization of the lysosomal membrane can have acute beneficial effects, supporting inflammation and antigen cross-presentation, sustained or repeated lysosomal perforations have adverse metabolic and transcriptional consequences and can lead to cell death. This review outlines factors contributing to lysosomal stress and damage perception, as well as remedial processes aimed at addressing lysosomal disruptions. We conclude that lysosomal stress plays widespread roles in human physiology and pathology, the understanding and manipulation of which can open the door to novel therapeutic strategies.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1425-1439"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522914","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}

引用次数: 0

Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-07 DOI: 10.1038/s44319-025-00373-0

Nefeli Skoufou-Papoutsaki, Sam Adler, Shenay Mehmed, Claire Tume, Cora Olpe, Edward Morrissey, Richard Kemp, Anne-Claire Girard, Elisa B Moutin, Chandra Sekhar Reddy Chilamakuri, Jodi L Miller, Cecilia Lindskog, Fabian Werle, Kate Marks, Francesca Perrone, Matthias Zilbauer, David S Tourigny, Douglas J Winton

{"title":"Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon.","authors":"Nefeli Skoufou-Papoutsaki, Sam Adler, Shenay Mehmed, Claire Tume, Cora Olpe, Edward Morrissey, Richard Kemp, Anne-Claire Girard, Elisa B Moutin, Chandra Sekhar Reddy Chilamakuri, Jodi L Miller, Cecilia Lindskog, Fabian Werle, Kate Marks, Francesca Perrone, Matthias Zilbauer, David S Tourigny, Douglas J Winton","doi":"10.1038/s44319-025-00373-0","DOIUrl":"10.1038/s44319-025-00373-0","url":null,"abstract":"Cancer driver mutations are defined by their high prevalence in cancers and presumed rarity in normal tissues. However, recent studies show that positive selection in normal epithelia can increase the prevalence of some cancer drivers. To determine their true cancer-driving potential, it is essential to evaluate how frequent these mutations are in normal tissues and what are their phenotypes. Here, we explore the bioavailability of somatic variants by quantifying age-related mutational burdens in normal human colonic epithelium using immunodetection in FFPE samples (N = 181 patients). Positive selection of variants of tumour suppressor genes PTEN and ARID1A associates with monoallelic gene loss as confirmed by CRISPR/Cas9 mutagenesis and changes in their downstream effectors. Comparison of the mutational burden in normal tissue and colorectal cancers allows quantification of cancer driver potency based on relative representation. Additionally, immune exclusion, a cancer hallmark feature, is observed within ARID1A-deficient clones in histologically normal tissue. The behaviour resulting from haploinsufficiency of PTEN and ARID1A demonstrates how somatic mosaicism of tumour suppressors arises and can predispose to cancer initiation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1269-1289"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370602","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}

引用次数: 0

c-di-GMP inhibits rRNA methylation and impairs ribosome assembly in the presence of kanamycin.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-01-27 DOI: 10.1038/s44319-025-00377-w

Siqi Yu, Zheyao Hu, Xiaoting Xu, Xiaoran Liang, Jiayi Shen, Min Liu, Mingxi Lin, Hong Chen, Jordi Marti, Sheng-Ce Tao, Zhaowei Xu

引用次数: 0

Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-01-28 DOI: 10.1038/s44319-025-00375-y

Ramy Rahmé, Lois Resnick-Silverman, Vincent Anguiano, Moray J Campbell, Pierre Fenaux, James J Manfredi

引用次数: 0

PIF/harbinger transposon-derived protein promotes 7SL expression to enhance pathogen resistance.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-01-30 DOI: 10.1038/s44319-025-00379-8

Shang Geng, Xing Lv, Tianjun Xu

引用次数: 0

AMPK activation by glycogen expenditure primes the exit of naïve pluripotency.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1038/s44319-025-00384-x

Seong-Min Kim, Eun-Ji Kwon, Ji-Young Oh, Han Sun Kim, Sunghyouk Park, Goo Jang, Jeong Tae Do, Keun-Tae Kim, Hyuk-Jin Cha

{"title":"AMPK activation by glycogen expenditure primes the exit of naïve pluripotency.","authors":"Seong-Min Kim, Eun-Ji Kwon, Ji-Young Oh, Han Sun Kim, Sunghyouk Park, Goo Jang, Jeong Tae Do, Keun-Tae Kim, Hyuk-Jin Cha","doi":"10.1038/s44319-025-00384-x","DOIUrl":"10.1038/s44319-025-00384-x","url":null,"abstract":"Embryonic and epiblast stem cells in pre-and post-implantation embryos are characterized by their naïve and primed states, respectively which represent distinct phases of pluripotency. Thus, cellular transition from naïve-to-primed pluripotency recapitulates a drastic metabolic and cellular remodeling after implantation to adapt to changes in extracellular conditions. Here, we found that inhibition of AMPK occurs during naïve transition with two conventional inhibitors of the MEK1 and GSK3β pathways. The accumulation of glycogen due to iGSK3β is responsible for AMPK inhibition, which accounts for high de novo fatty acid synthesis in naïve (ESCs). The knockout of glycogen synthase 1 in naïve ESCs; GKO, resulting in a drastic glycogen loss, leads to a robust AMPK activation and lowers the level of fatty acids. GKO loses cellular characteristics of naïve ESCs and rapidly transitioned to a primed state. The characteristics of GKO are restored by the simultaneous AMPK KO. These findings suggest that high glycogen in epiblast within pre-implantation blastocyst may act as a signaling molecule for timely activation of AMPK, thus ultimately contributing to transition to post-implantation stage epiblast.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1504-1527"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439546","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}

引用次数: 0

The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-01-27 DOI: 10.1038/s44319-025-00374-z

Jung Jennifer Ho, Edith Cheng, Cassandra J Wong, Jonathan R St-Germain, Wade H Dunham, Brian Raught, Anne-Claude Gingras, Grant W Brown

{"title":"The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges.","authors":"Jung Jennifer Ho, Edith Cheng, Cassandra J Wong, Jonathan R St-Germain, Wade H Dunham, Brian Raught, Anne-Claude Gingras, Grant W Brown","doi":"10.1038/s44319-025-00374-z","DOIUrl":"10.1038/s44319-025-00374-z","url":null,"abstract":"Homologous recombination is a largely error-free DNA repair mechanism conserved across all domains of life and is essential for the maintenance of genome integrity. Not only are the mutations in homologous recombination repair genes probable cancer drivers, some also cause genetic disorders. In particular, mutations in the Bloom (BLM) helicase cause Bloom Syndrome, a rare autosomal recessive disorder characterized by increased sister chromatid exchanges and predisposition to a variety of cancers. The pathology of Bloom Syndrome stems from the impaired activity of the BLM-TOP3A-RMI1-RMI2 (BTRR) complex which suppresses crossover recombination to prevent potentially deleterious genome rearrangements. We provide a comprehensive BTRR proximal proteome, revealing proteins that suppress crossover recombination. We find that RAD54L2, a SNF2-family protein, physically interacts with BLM and suppresses sister chromatid exchanges. RAD54L2 is important for recruitment of BLM to chromatin and requires an intact ATPase domain to promote non-crossover recombination. Thus, the BTRR proximity map identifies a regulator of recombination.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1290-1314"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052068","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}

引用次数: 0

Short internal open reading frames repress the translation of N-terminally truncated proteoforms.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1038/s44319-025-00390-z

Raphael Fettig, Zita Gonda, Niklas Walter, Paul Sallmann, Christiane Thanisch, Markus Winter, Susanne Bauer, Lei Zhang, Greta Linden, Margarethe Litfin, Marina Khamanaeva, Sarah Storm, Christina Münzing, Christelle Etard, Olivier Armant, Olalla Vázquez, Olivier Kassel

{"title":"Short internal open reading frames repress the translation of N-terminally truncated proteoforms.","authors":"Raphael Fettig, Zita Gonda, Niklas Walter, Paul Sallmann, Christiane Thanisch, Markus Winter, Susanne Bauer, Lei Zhang, Greta Linden, Margarethe Litfin, Marina Khamanaeva, Sarah Storm, Christina Münzing, Christelle Etard, Olivier Armant, Olalla Vázquez, Olivier Kassel","doi":"10.1038/s44319-025-00390-z","DOIUrl":"10.1038/s44319-025-00390-z","url":null,"abstract":"Internal translation initiation sites, as revealed by ribosome profiling experiments can potentially drive the translation of many N-terminally truncated proteoforms. We report that internal short open reading frame (sORF) within coding sequences regulate their translation. nTRIP6 represents a short nuclear proteoform of the cytoplasmic protein TRIP6. We have previously reported that nTRIP6 regulates the dynamics of skeletal muscle progenitor differentiation. Here we show that nTRIP6 is generated by translation initiation at an internal AUG after leaky scanning at the canonical TRIP6 AUG. The translation of nTRIP6 is repressed by an internal sORF immediately upstream of the nTRIP6 AUG. Consistent with this representing a more general regulatory feature, we have identified other internal sORFs which repress the translation of N-terminally truncated proteoforms. In an in vitro model of myogenic differentiation, the expression of nTRIP6 is transiently upregulated through a mechanistic Target of Rapamycin Complex 1-dependent increase in translation initiation at the internal AUG. Thus, the translation of N-terminally truncated proteoforms can be regulated independently of the canonical ORF.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1566-1589"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439959","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}

引用次数: 0

Author Correction: Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 DOI: 10.1038/s44319-025-00408-6

Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin

引用次数: 0

Viral oncogene EBNALP regulates YY1 DNA binding and alters host 3D genome organization. 病毒癌基因EBNALP调节YY1 DNA结合并改变宿主三维基因组组织。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00357-6

Chong Wang, Merrin Manlong Leong, Weiyue Ding, Yohei Narita, Xiang Liu, Hongbo Wang, Stefanie P T Yiu, Jessica Lee, Katelyn R S Zhao, Amy Cui, Benjamin Gewurz, Wolfgang Hammerschmidt, Mingxiang Teng, Bo Zhao

{"title":"Viral oncogene EBNALP regulates YY1 DNA binding and alters host 3D genome organization.","authors":"Chong Wang, Merrin Manlong Leong, Weiyue Ding, Yohei Narita, Xiang Liu, Hongbo Wang, Stefanie P T Yiu, Jessica Lee, Katelyn R S Zhao, Amy Cui, Benjamin Gewurz, Wolfgang Hammerschmidt, Mingxiang Teng, Bo Zhao","doi":"10.1038/s44319-024-00357-6","DOIUrl":"10.1038/s44319-024-00357-6","url":null,"abstract":"The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNALP) is essential for the immortalization of naive B lymphocytes (NBLs). However, the mechanisms remain elusive. To understand EBNALP's role in B-cell transformation, we compare NBLs infected with wild-type EBV and an EBNALP-null mutant EBV using multi-omics techniques. EBNALP inactivation alters enhancer-promoter interactions, resulting in decreased CCND2 and increased CASP1 and BCL2L11 expression. Mechanistically, EBNALP interacts with and colocalizes with the looping factor YY1. Depletion of EBNALP reduces YY1 DNA-binding and enhancer-promoter interactions, similar to effects observed with YY1 depletion. Furthermore, EBNALP colocalizes with DPF2, a protein that binds to H3K14ac and H4K16ac. CRISPR depletion of DPF2 reduces both EBNALP and YY1 DNA binding, suggesting that the DPF2/EBNALP complex may tether YY1 to DNA to increase enhancer-promoter interactions. EBNALP inactivation also increases enhancer-promoter interactions at the CASP1 and BCL2L11 loci, along with elevated DPF2 and YY1 binding and DNA accessibility. Our data suggest that EBNALP regulates YY1 to rewire the host genome, which might facilitate naive B-cell transformation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"810-835"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921165","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}

引用次数: 0