bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–07–21
fourteen papers selected by
Valentina Piano, Uniklinik Köln
  1. CCDC68 Maintains Mitotic Checkpoint Activation by Promoting CDC20 Integration into the MCC.
  2. PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis.
  3. TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes.
  4. Proteomic analysis reveals a PLK1-dependent G2/M degradation program and a role for AKAP2 in coordinating the mitotic cytoskeleton.
  5. Centrosome age breaks spindle size symmetry even in cells thought to divide symmetrically.
  6. The polySUMOylation axis promotes nucleolar release of Tof2 for mitotic exit.
  7. Maternal inheritance of functional centrioles in two parthenogenetic nematodes.
  8. Live chromosome identifying and tracking reveals size-based spatial pathway of meiotic errors in oocytes.
  9. BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.
  10. APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.
  11. A deterministic, c-di-GMP-dependent program ensures the generation of phenotypically similar, symmetric daughter cells during cytokinesis.
  12. Predicting Infertility: How Genetic Variants in Oocyte Spindle Genes Affect Egg Quality.
  13. Msc1 is a nuclear envelope protein that reinforces DNA repair in late mitosis.
  14. Rational correction of pathogenic conformational defects in HTRA1.
  1. Adv Sci (Weinh). 2024 Jul 17. e2406009
    CCDC68 Maintains Mitotic Checkpoint Activation by Promoting CDC20 Integration into the MCC.
    Qi Li, Qingzhou Chen, Tao Zheng, Fulin Wang, Junlin Teng, Haining Zhou, Jianguo Chen.
      The spindle assembly checkpoint (SAC) ensures chromosome segregation fidelity by manipulating unattached kinetochore-dependent assembly of the mitotic checkpoint complex (MCC). The MCC binds to and inhibits the anaphase promoting complex/cyclosome (APC/C) to postpone mitotic exit. However, the mechanism by which unattached kinetochores mediate MCC formation is not yet fully understood. Here, it is shown that CCDC68 is an outer kinetochore protein that preferentially localizes to unattached kinetochores. Furthermore, CCDC68 interacts with the SAC factor CDC20 to inhibit its autoubiquitination and MCC disassembly. Therefore, CCDC68 restrains APC/C activation to ensure a robust SAC and allow sufficient time for chromosome alignment, thus ensuring chromosomal stability. Hence, the study reveals that CCDC68 is required for CDC20-dependent MCC stabilization to maintain mitotic checkpoint activation.
    Keywords:  CCDC68; CDC20; kinetochore; mitotic checkpoint complex; spindle assembly checkpoint
    DOI:  https://doi.org/10.1002/advs.202406009
  2. Cell Rep. 2024 Jul 13. pii: S2211-1247(24)00823-4. [Epub ahead of print]43(7): 114494
    PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis.
    María Sanz-Flores, Miguel Ruiz-Torres, Cristina Aguirre-Portolés, Aicha El Bakkali, Beatriz Salvador-Barberó, Carolina Villarroya-Beltri, Sagrario Ortega, Diego Megías, Daniel W Gerlich, Mónica Álvarez-Fernández, Marcos Malumbres.
      Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.
    Keywords:  B55; CP: Cell biology; CP: Molecular biology; Ki-67; PP2A; PPP2R2A; PPP2R2D; cell division; chromosome clustering; chromosome periphery; mitosis; phosphatase
    DOI:  https://doi.org/10.1016/j.celrep.2024.114494
  3. EMBO J. 2024 Jul 16.
    TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes.
    Srijita Paul Chowdhuri, Benu Brata Das.
      Topoisomerase 1 (Top1) controls DNA topology, relieves DNA supercoiling during replication and transcription, and is critical for mitotic progression to the G1 phase. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1cc). Here, we identify CDK1-dependent phosphorylation of TDP1 at residue S61 during mitosis. A TDP1 variant defective for S61 phosphorylation (TDP1-S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via a MUS81-dependent DNA repair mechanism. Replication stress induced by camptothecin or aphidicolin leads to TDP1-S61A enrichment at common fragile sites, which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in the formation of 53BP1 nuclear bodies during G1 phase. Our findings provide new insights into the cell cycle-dependent regulation of TDP1 dynamics for the repair of trapped Top1-DNA covalent complexes during mitosis that prevents genomic instability following replication stress.
    Keywords:  CDK1; MUS81; MiDAS; TDP1; Topoisomerase 1
    DOI:  https://doi.org/10.1038/s44318-024-00169-3
  4. Cell Rep. 2024 Jul 16. pii: S2211-1247(24)00839-8. [Epub ahead of print]43(8): 114510
    Proteomic analysis reveals a PLK1-dependent G2/M degradation program and a role for AKAP2 in coordinating the mitotic cytoskeleton.
    Ryan D Mouery, Kimberly Lukasik, Carolyn Hsu, Thomas Bonacci, Derek L Bolhuis, Xianxi Wang, C Allie Mills, E Drew Toomer, Owen G Canterbury, Kevin C Robertson, Timothy B Branigan, Nicholas G Brown, Laura E Herring, Stephanie L Gupton, Michael J Emanuele.
      Ubiquitination is an essential regulator of cell division. The kinase Polo-like kinase 1 (PLK1) promotes protein degradation at G2/M phase through the E3 ubiquitin ligase Skp1-Cul1-F box (SCF)βTrCP. However, the magnitude to which PLK1 shapes the mitotic proteome is uncharacterized. Combining quantitative proteomics with pharmacologic PLK1 inhibition revealed a widespread, PLK1-dependent program of protein breakdown at G2/M. We validated many PLK1-regulated proteins, including substrates of the cell-cycle E3 SCFCyclin F, demonstrating that PLK1 promotes proteolysis through at least two distinct E3 ligases. We show that the protein-kinase-A-anchoring protein A-kinase anchor protein 2 (AKAP2) is cell-cycle regulated and that its mitotic degradation is dependent on the PLK1/βTrCP signaling axis. Expression of a non-degradable AKAP2 mutant resulted in actin defects and aberrant mitotic spindles, suggesting that AKAP2 degradation coordinates cytoskeletal organization during mitosis. These findings uncover PLK1's far-reaching role in shaping the mitotic proteome post-translationally and have potential implications in malignancies where PLK1 is upregulated.
    Keywords:  AKAP2; CP: Cell biology; CP: Molecular biology; Cullin RING Ligase; Cyclin F; G2/M; Plk1; cell cycle; mitosis; protein degradation; ubiquitin; βTRCP
    DOI:  https://doi.org/10.1016/j.celrep.2024.114510
  5. J Cell Biol. 2024 Aug 05. pii: e202311153. [Epub ahead of print]223(8):
    Centrosome age breaks spindle size symmetry even in cells thought to divide symmetrically.
    Alexandre Thomas, Patrick Meraldi.
      Centrosomes are the main microtubule-organizing centers in animal cells. Due to the semiconservative nature of centrosome duplication, the two centrosomes differ in age. In asymmetric stem cell divisions, centrosome age can induce an asymmetry in half-spindle lengths. However, whether centrosome age affects the symmetry of the two half-spindles in tissue culture cells thought to divide symmetrically is unknown. Here, we show that in human epithelial and fibroblastic cell lines centrosome age imposes a mild spindle asymmetry that leads to asymmetric cell daughter sizes. At the mechanistic level, we show that this asymmetry depends on a cenexin-bound pool of the mitotic kinase Plk1, which favors the preferential accumulation on old centrosomes of the microtubule nucleation-organizing proteins pericentrin, γ-tubulin, and Cdk5Rap2, and microtubule regulators TPX2 and ch-TOG. Consistently, we find that old centrosomes have a higher microtubule nucleation capacity. We postulate that centrosome age breaks spindle size symmetry via microtubule nucleation even in cells thought to divide symmetrically.
    DOI:  https://doi.org/10.1083/jcb.202311153
  6. Cell Rep. 2024 Jul 11. pii: S2211-1247(24)00821-0. [Epub ahead of print]43(7): 114492
    The polySUMOylation axis promotes nucleolar release of Tof2 for mitotic exit.
    Emily Gutierrez-Morton, Cory Haluska, Liam Collins, Raed Rizkallah, Robert J Tomko, Yanchang Wang.
      In budding yeast, the nucleolus serves as the site to sequester Cdc14, a phosphatase essential for mitotic exit. Nucleolar proteins Tof2, Net1, and Fob1 are required for this sequestration. Although it is known that these nucleolar proteins are SUMOylated, how SUMOylation regulates their activity remains unknown. Here, we show that Tof2 exhibits cell-cycle-regulated nucleolar delocalization and turnover. Depletion of the nuclear small ubiquitin-like modifier (SUMO) protease Ulp2 not only causes Tof2 polySUMOylation, nucleolar delocalization, and degradation but also leads to Cdc14 nucleolar release and activation. This outcome depends on polySUMOylation and the activity of downstream enzymes, including SUMO-targeted ubiquitin ligase and Cdc48/p97 segregase. We further developed a system to tether SUMO machinery to Tof2 and generated a SUMO-deficient tof2 mutant, and the results indicate that Tof2 polySUMOylation is necessary and sufficient for its nucleolar delocalization and degradation. Together, our work reveals a polySUMO-dependent mechanism that delocalizes Tof2 from the nucleolus to facilitate mitotic exit.
    Keywords:  CP: Cell biology; Cdc14; Cdc48/p97/VCP; STUbL; SUMOylation; Tof2; cell cycle; mitotic exit; nucleolus; polySUMOylation; yeast
    DOI:  https://doi.org/10.1016/j.celrep.2024.114492
  7. Nat Commun. 2024 Jul 18. 15(1): 6042
    Maternal inheritance of functional centrioles in two parthenogenetic nematodes.
    Aurélien Perrier, Nadège Guiglielmoni, Delphine Naquin, Kevin Gorrichon, Claude Thermes, Sonia Lameiras, Alexander Dammermann, Philipp H Schiffer, Maia Brunstein, Julie C Canman, Julien Dumont.
      Centrioles are the core constituent of centrosomes, microtubule-organizing centers involved in directing mitotic spindle assembly and chromosome segregation in animal cells. In sexually reproducing species, centrioles degenerate during oogenesis and female meiosis is usually acentrosomal. Centrioles are retained during male meiosis and, in most species, are reintroduced with the sperm during fertilization, restoring centriole numbers in embryos. In contrast, the presence, origin, and function of centrioles in parthenogenetic species is unknown. We found that centrioles are maternally inherited in two species of asexual parthenogenetic nematodes and identified two different strategies for maternal inheritance evolved in the two species. In Rhabditophanes diutinus, centrioles organize the poles of the meiotic spindle and are inherited by both the polar body and embryo. In Disploscapter pachys, the two pairs of centrioles remain close together and are inherited by the embryo only. Our results suggest that maternally-inherited centrioles organize the embryonic spindle poles and act as a symmetry-breaking cue to induce embryo polarization. Thus, in these parthenogenetic nematodes, centrioles are maternally-inherited and functionally replace their sperm-inherited counterparts in sexually reproducing species.
    DOI:  https://doi.org/10.1038/s41467-024-50427-5
  8. Science. 2024 Jul 19. 385(6706): eadn5529
    Live chromosome identifying and tracking reveals size-based spatial pathway of meiotic errors in oocytes.
    Osamu Takenouchi, Yogo Sakakibara, Tomoya S Kitajima.
      Meiotic errors of relatively small chromosomes in oocytes result in egg aneuploidies that cause miscarriages and congenital diseases. Unlike somatic cells, which preferentially mis-segregate larger chromosomes, aged oocytes preferentially mis-segregate smaller chromosomes through unclear processes. Here, we provide a comprehensive three-dimensional chromosome identifying-and-tracking dataset throughout meiosis I in live mouse oocytes. This analysis reveals a prometaphase pathway that actively moves smaller chromosomes to the inner region of the metaphase plate. In the inner region, chromosomes are pulled by stronger bipolar microtubule forces, which facilitates premature chromosome separation, a major cause of segregation errors in aged oocytes. This study reveals a spatial pathway that facilitates aneuploidy of small chromosomes preferentially in aged eggs and implicates the role of the M phase in creating a chromosome size-based spatial arrangement.
    DOI:  https://doi.org/10.1126/science.adn5529
  9. J Biomed Sci. 2024 Jul 16. 31(1): 74
    BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.
    Maria P Silva, Luísa T Ferreira, Natércia F Brás, Lurdes Torres, Andreia Brandão, Manuela Pinheiro, Marta Cardoso, Adriana Resende, Joana Vieira, Carlos Palmeira, Gabriela Martins, Miguel Silva, Carla Pinto, Ana Peixoto, João Silva, Rui Henrique, Sofia Maia, Helder Maiato, Manuel R Teixeira, Paula Paulo.
       BACKGROUND: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis.
    METHODS: To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes.
    RESULTS: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies.
    CONCLUSIONS: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.
    Keywords:   BUB1B ; BubR1; Cancer predisposition; Chromosomal instability; Premature chromatid separation; Taxol response
    DOI:  https://doi.org/10.1186/s12929-024-01056-z
  10. Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2319574121
    APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.
    Brandon L Mouery, Eliyambuya M Baker, Liu Mei, Samuel C Wolff, Christine A Mills, Dalia Fleifel, Nebyou Mulugeta, Laura E Herring, Jeanette Gowen Cook.
      Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.
    Keywords:  anaphase promoting complex/cyclosome (APC/C); breast cancer; cell cycle arrest; cyclin-dependent kinase 4/6 (CDK4/6); genome instability
    DOI:  https://doi.org/10.1073/pnas.2319574121
  11. Nat Commun. 2024 Jul 17. 15(1): 6014
    A deterministic, c-di-GMP-dependent program ensures the generation of phenotypically similar, symmetric daughter cells during cytokinesis.
    María Pérez-Burgos, Marco Herfurth, Andreas Kaczmarczyk, Andrea Harms, Katrin Huber, Urs Jenal, Timo Glatter, Lotte Søgaard-Andersen.
      Phenotypic heterogeneity in bacteria can result from stochastic processes or deterministic programs. The deterministic programs often involve the versatile second messenger c-di-GMP, and give rise to daughter cells with different c-di-GMP levels by deploying c-di-GMP metabolizing enzymes asymmetrically during cell division. By contrast, less is known about how phenotypic heterogeneity is kept to a minimum. Here, we identify a deterministic c-di-GMP-dependent program that is hardwired into the cell cycle of Myxococcus xanthus to minimize phenotypic heterogeneity and guarantee the formation of phenotypically similar daughter cells during division. Cells lacking the diguanylate cyclase DmxA have an aberrant motility behaviour. DmxA is recruited to the cell division site and its activity is switched on during cytokinesis, resulting in a transient increase in the c-di-GMP concentration. During cytokinesis, this c-di-GMP burst ensures the symmetric incorporation and allocation of structural motility proteins and motility regulators at the new cell poles of the two daughters, thereby generating phenotypically similar daughters with correct motility behaviours. Thus, our findings suggest a general c-di-GMP-dependent mechanism for minimizing phenotypic heterogeneity, and demonstrate that bacteria can ensure the formation of dissimilar or similar daughter cells by deploying c-di-GMP metabolizing enzymes to distinct subcellular locations.
    DOI:  https://doi.org/10.1038/s41467-024-50444-4
  12. Adv Anat Embryol Cell Biol. 2024 ;238 1-22
    Predicting Infertility: How Genetic Variants in Oocyte Spindle Genes Affect Egg Quality.
    Leelabati Biswas, Karen Schindler.
      Successful reproduction relies on the union of a single chromosomally normal egg and sperm. Chromosomally normal eggs develop from precursor cells, called oocytes, that have undergone accurate chromosome segregation. The process of chromosome segregation is governed by the oocyte spindle, a unique cytoskeletal machine that splits chromatin content of the meiotically dividing oocyte. The oocyte spindle develops and functions in an idiosyncratic process, which is vulnerable to genetic variation in spindle-associated proteins. Human genetic variants in several spindle-associated proteins are associated with poor clinical fertility outcomes, suggesting that heritable etiologies for oocyte dysfunction leading to infertility exist and that the spindle is a crux for female fertility. This chapter examines the mammalian oocyte spindle through the lens of human genetic variation, covering the genes TUBB8, TACC3, CEP120, AURKA, AURKC, AURKB, BUB1B, and CDC20. Specifically, it explores how patient-identified variants perturb spindle development and function, and it links these molecular changes in the oocyte to their cognate clinical consequences, such as oocyte maturation arrest, elevated egg aneuploidy, primary ovarian insufficiency, and recurrent pregnancy loss. This discussion demonstrates that small genetic errors in oocyte meiosis can result in remarkably far-ranging embryonic consequences, and thus reveals the importance of the oocyte's fine machinery in sustaining life.
    Keywords:  Biomarkers; Egg; Fertility; Genetic variants; Genomics; In vitro fertilization; Infertility; Meiosis; Miscarriage; Mutation; Oocyte; Precision medicine; Pregnancy; Reproduction; Reproductive endocrinology; Reproductive medicine; Spindle; Spontaneous abortion
    DOI:  https://doi.org/10.1007/978-3-031-55163-5_1
  13. iScience. 2024 Jul 19. 27(7): 110250
    Msc1 is a nuclear envelope protein that reinforces DNA repair in late mitosis.
    Sara Medina-Suárez, Jessel Ayra-Plasencia, Lara Pérez-Martínez, Falk Butter, Félix Machín.
      Precise double-strand break (DSB) repair is a paramount for genome stability. Homologous recombination (HR) repairs DSBs when cyclin-dependent kinase (CDK) activity is high, which correlates with the availability of the sister chromatid as a template. However, anaphase and telophase are paradoxical scenarios since high CDK favors HR despite sister chromatids being no longer aligned. To identify factors specifically involved in DSB repair in late mitosis, we have undertaken comparative proteomics in Saccharomyces cerevisiae and found that meiotic sister chromatid 1 (Msc1), a poorly characterized nuclear envelope protein, is significantly enriched upon both random and guided DSBs. We further show that Δmsc1 is more sensitive to DSBs in late mitosis, and has a delayed repair of DBSs, as indicated by increased Rad53 hyperphosphorylation, a higher presence of RPA foci, fewer Rad52 repair factories, and slower HR completion. We propose that Msc1 favors the later stages of HR and the timely completion of DSB repair before cytokinesis.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110250
  14. Nat Commun. 2024 Jul 16. 15(1): 5944
    Rational correction of pathogenic conformational defects in HTRA1.
    Nathalie Beaufort, Linda Ingendahl, Melisa Merdanovic, Andree Schmidt, David Podlesainski, Tim Richter, Thorben Neumann, Michael Kuszner, Ingrid R Vetter, Patricia Stege, Steven G Burston, Anto Filipovic, Yasser B Ruiz-Blanco, Kenny Bravo-Rodriguez, Joel Mieres-Perez, Christine Beuck, Stephan Uebel, Monika Zobawa, Jasmin Schillinger, Rainer Malik, Katalin Todorov-Völgyi, Juliana Rey, Annabell Roberti, Birte Hagemeier, Benedikt Wefers, Stephan A Müller, Wolfgang Wurst, Elsa Sanchez-Garcia, Alexander Zimmermann, Xiao-Yu Hu, Tim Clausen, Robert Huber, Stefan F Lichtenthaler, Carsten Schmuck, Michael Giese, Markus Kaiser, Michael Ehrmann, Martin Dichgans.
      Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.
    DOI:  https://doi.org/10.1038/s41467-024-49982-8
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