Daxiao Sun#, Xueping Zhao, Tina Wiegand, Cécilie Martin-Lemaitre, Tom Borianne, Lennart Kleinschmidt, Stephan W. Grill, Anthony Hyman, Christoph A. Weber#, Alf Honigmann# Assembly of tight junction belts by ZO1 surface condensation and local actin polymerization. Dev Cell, Art. No. doi: 10.1016/j.devcel.2024.12.012 (2025)
Open Access DOI
Tight junctions play an essential role in sealing tissues, by forming belts of adhesion strands around cellular perimeters. Recent work has shown that the condensation of ZO1 scaffold proteins is required for tight junction assembly. However, the mechanisms by which junctional condensates initiate at cell-cell contacts and elongate around cell perimeters remain unknown. Combining biochemical reconstitutions and live-cell imaging of MDCKII tissue, we found that tight junction belt formation is driven by adhesion receptor-mediated ZO1 surface condensation coupled to local actin polymerization. Adhesion receptor oligomerization provides the signal for surface binding and local condensation of ZO1 at the cell membrane. Condensation produces a molecular scaffold that selectively enriches junctional proteins. Finally, ZO1 condensates directly facilitate local actin polymerization and filament bundling, driving the elongation into a continuous tight junction belt. More broadly, our work identifies how cells couple surface condensation with cytoskeleton organization to assemble and structure adhesion complexes.
Anne Grapin-Botton#, Jonathan Y-H Loh# Editorial overview: Regaining architecture and cell cross-talk upon regeneration. Curr Opin Genet Dev, 91 Art. No. 102302 (2025) DOI
Max Dongsheng Yin✳︎, Olivier N Lemaire✳︎, José Guadalupe Rosas Jiménez, Mélissa Belhamri, Anna Shevchenko, Gerhard Hummer#, Tristan Wagner#, Bonnie J Murphy# Conformational dynamics of a multienzyme complex in anaerobic carbon fixation. Science, 387(6733) 498-504 (2025) DOI
In the ancient microbial Wood-Ljungdahl pathway, carbon dioxide (CO2) is fixed in a multistep process that ends with acetyl-coenzyme A (acetyl-CoA) synthesis at the bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). In this work, we present structural snapshots of the CODH/ACS from the gas-converting acetogen Clostridium autoethanogenum, characterizing the molecular choreography of the overall reaction, including electron transfer to the CODH for CO2 reduction, methyl transfer from the corrinoid iron-sulfur protein (CoFeSP) partner to the ACS active site, and acetyl-CoA production. Unlike CODH, the multidomain ACS undergoes large conformational changes to form an internal connection to the CODH active site, accommodate the CoFeSP for methyl transfer, and protect the reaction intermediates. Altogether, the structures allow us to draw a detailed reaction mechanism of this enzyme, which is crucial for CO2 fixation in anaerobic organisms.
Srustidhar Das, S Martina Parigi, Xinxin Luo, Jennifer Fransson, Bianca C Kern, Ali Okhovat, Oscar E Diaz, Chiara Sorini, Paulo Czarnewski, Anna T Webb, Rodrigo A Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J Villablanca Liver X receptor unlinks intestinal regeneration and tumorigenesis. Nature, 637(8048) 1198-1206 (2025)
Open Access DOI
Uncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
Ariadna E Morales✳︎, Yue Dong✳︎, Thomas Brown, Kaushal Baid, Dimitrios-Georgios Kontopoulos, Victoria Gonzalez, Zixia Huang, Alexis-Walid Ahmed, Arkadeb Bhuinya, Leon Hilgers, Sylke Winkler, Graham M Hughes, Xiaomeng Li, Ping Lu, Yixin Yang, Bogdan Kirilenko, Paolo Devanna, Tanya M Lama, Yomiran Nissan, Martin Pippel, Liliana M Dávalos, Sonja Vernes, Sébastien J Puechmaille, Stephen J Rossiter, Yossi Yovel, Joseph B Prescott, Andreas Kurth, David A Ray, Burton K Lim, Eugene W Myers, Emma Teeling, Arinjay Banerjee, Aaron T Irving#, Michael Hiller# Bat genomes illuminate adaptations to viral tolerance and disease resistance. Nature, Art. No. doi: 10.1038/s41586-024-08471-0 (2025)
Open Access DOI
Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order1. Infections in bats are largely asymptomatic2,3, indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. 4,5), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species-specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15, separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.
Aditya Chhatre, Ludek Stepanek, Adrian Pascal Nievergelt, Gonzalo Alvarez Viar, Stefan Diez#, Gaia Pigino# Tubulin tyrosination/detyrosination regulate the affinity and sorting of intraflagellar transport trains on axonemal microtubule doublets. Nat Commun, 16(1) Art. No. 1055 (2025)
Open Access DOI
Cilia assembly and function rely on the bidirectional transport of components between the cell body and ciliary tip via Intraflagellar Transport (IFT) trains. Anterograde and retrograde IFT trains travel along the B- and A-tubules of microtubule doublets, respectively, ensuring smooth traffic flow. However, the mechanism underlying this segregation remains unclear. Here, we test whether tubulin detyrosination (enriched on B-tubules) and tyrosination (enriched on A-tubules) have a role in IFT logistics. We report that knockout of tubulin detyrosinase VashL in Chlamydomonas reinhardtii causes frequent IFT train stoppages and impaired ciliary growth. By reconstituting IFT train motility on de-membranated axonemes and synthetic microtubules, we show that anterograde and retrograde trains preferentially associate with detyrosinated and tyrosinated microtubules, respectively. We propose that tubulin tyrosination/detyrosination is crucial for spatial segregation and collision-free IFT train motion, highlighting the significance of the tubulin code in ciliary transport.
Yaw Asare#, Guangyao Yan, Christina Schlegl, Matthias Prestel, Emiel P C van der Vorst, Abraham J P Teunissen, Arailym Aronova, Federica Tosato, Nawraa Naser, Julio Caputo, Geoffrey Prevot, Anthony Azzun, Benedikt Wefers, Wolfgang Wurst, Melanie Schneider, Ignasi Forne, Kiril Bidzhekov, Ronald Naumann, Sander W van der Laan, Markus Brandhofer, Jiayu Cao, Stefan Roth, Rainer Malik, Steffen Tiedt, Willem J M Mulder, Axel Imhof, Arthur Liesz, Christian Weber, Jürgen Bernhagen, Martin Dichgans# A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis. Immunity, Art. No. doi: 10.1016/j.immuni.2025.01.003 (2025)
Open Access DOI
Common genetic variants in a conserved cis-regulatory element (CRE) at histone deacetylase (HDAC)9 are a major risk factor for cardiovascular disease, including stroke and coronary artery disease. Given the consistency of this association and its proinflammatory properties, we examined the mechanisms whereby HDAC9 regulates vascular inflammation. HDAC9 bound and mediated deacetylation of NLRP3 in the NACHT and LRR domains leading to inflammasome activation and lytic cell death. Targeted deletion of the critical CRE in mice increased Hdac9 expression in myeloid cells to exacerbate inflammasome-dependent chronic inflammation. In human carotid endarterectomy samples, increased HDAC9 expression was associated with atheroprogression and clinical plaque instability. Incorporation of TMP195, a class IIa HDAC inhibitor, into lipoprotein-based nanoparticles to target HDAC9 at the site of myeloid-driven vascular inflammation stabilized atherosclerotic plaques, implying a lower risk of plaque rupture and cardiovascular events. Our findings link HDAC9 to atherogenic inflammation and provide a paradigm for anti-inflammatory therapeutics for atherosclerosis.
Thomas Brown, Ketan Mishra, Ahmed Elewa, Svetlana Iarovenko, Elaiyaraja Subramanian, Alberto Joven Araus, Andreas Petzold, Bastian Fromm, Marc R Friedländer, Lennart Rikk, Miyuki Suzuki, Ken-Ichi T Suzuki, Toshinori Hayashi, Atsushi Toyoda, Catarina Oliveira, Ekaterina Osipova, Nicholas D Leigh#, Maximina H Yun#, András Simon# Chromosome-scale genome assembly reveals how repeat elements shape non-coding RNA landscapes active during newt limb regeneration. Cell Genom, Art. No. doi: 10.1016/j.xgen.2025.100761 (2025)
Open Access DOI
Newts have large genomes harboring many repeat elements. How these elements shape the genome and relate to newts' unique regeneration ability remains unknown. We present here the chromosome-scale assembly of the 20.3 Gb genome of the Iberian ribbed newt, Pleurodeles waltl, with a hitherto unprecedented contiguity and completeness among giant genomes. Utilizing this assembly, we demonstrate conserved synteny as well as genetic rearrangements, such as in the major histocompatibility complex locus. We provide evidence suggesting that intronic repeat elements drive newt-specific circular RNA (circRNA) biogenesis and show their regeneration-specific expression. We also present a comprehensive in-depth annotation and chromosomal mapping of microRNAs, highlighting genomic expansion profiles as well as a distinct regulatory pattern in the regenerating limb. These data reveal links between repeat elements, non-coding RNAs, and adult regeneration and provide key resources for addressing developmental, regenerative, and evolutionary principles.
A Sophie Brumm, Afshan McCarthy, Claudia Gerri, Todd Fallesen, Laura Woods, Riley McMahon, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Paul Serhal, Rabi A Odia, Mina Vasilic, Anna Osnato, Peter J Rugg-Gunn, Ludovic Vallier, Caroline S Hill, Kathy K Niakan Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling. Dev Cell, 60(2) 174-185 (2025)
Open Access DOI
The human blastocyst contains the pluripotent epiblast from which human embryonic stem cells (hESCs) can be derived. ACTIVIN/NODAL signaling maintains expression of the transcription factor NANOG and in vitro propagation of hESCs. It is unknown whether this reflects a functional requirement for epiblast development in human embryos. Here, we characterized NODAL signaling activity during pre-implantation human development. We showed that NANOG is an early molecular marker restricted to the nascent human pluripotent epiblast and was initiated prior to the onset of NODAL signaling. We further demonstrated that expression of pluripotency-associated transcription factors NANOG, SOX2, OCT4, and KLF17 were maintained in the epiblast in the absence of NODAL signaling activity. Genome-wide transcriptional analysis showed that NODAL signaling inhibition did not decrease NANOG transcription or impact the wider pluripotency-associated gene regulatory network. These data suggest differences in the signaling requirements regulating pluripotency in the pre-implantation human epiblast compared with existing hESC culture.
Mitsuhiro Matsuda#, Jorge Lázaro, Miki Ebisuya# Metabolic activities are selective modulators for individual segmentation clock processes. Nat Commun, 16(1) Art. No. 845 (2025)
Open Access DOI
Numerous cellular and molecular processes during embryonic development prompt the fundamental question of how their tempos are coordinated and whether a common global modulator exists. While the segmentation clock tempo scales with the kinetics of gene expression and degradation processes of the core clock gene Hes7 across mammals, the coordination of these processes remains unclear. This study examines whether metabolic activities serve as a global modulator for the segmentation clock, finding them to be selective instead. Several metabolic inhibitions extend the clock period but affect key processes differently: glycolysis inhibition slows Hes7 protein degradation and production delay without altering intron delay, while electron transport chain inhibition extends intron delay without influencing the other processes. Combinations of distinct metabolic inhibitions exhibit synergistic effects. We propose that the scaled kinetics of segmentation clock processes across species may result from combined selective modulators shaped by evolutionary constraints, rather than a single global modulator.