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Dworak, Helene; Rozmaric, Tomaz; Grillari, Johannes; Ogrodnik, Mikolaj
doi: 10.1002/1873-3468.70037pmid: 40156464
Biological processes are often spatially regulated, ensuring molecular and cellular events occur in their most strategically advantageous locations. Cellular senescence, marked by cell cycle arrest and hypersecretion, is recognized as an important part of physiological processes like development and healing, but it also contributes to aging and disease. However, the spatial distribution of senescent cells and its physiological and pathological impact remain unclear. Here we compile evidence on senescent cell localization in development, healing, and aging. We emphasize the significance of their spatial patterns and speculate on the effects of disrupted spatial positioning of senescence in relation to pathologies. To summarize the specific spatial functions of senescent cells, we propose to refer to them as ‘barrier’ and ‘conductor’ functions. The ‘barrier’ function of senescent cells, due to their altered morphology and apoptosis resistance, separates tissues and builds a border between two environments. The conductor function, with the secretion of signaling factors, influences the surrounding area and stimulates migration, differentiation, or proliferation, among other processes. Overall, this Review explores the spatial patterning of cellular senescence in biological processes, highlighting its dual roles as ‘barrier’ and ‘conductor’ functions, and examines the implications of senescent cell distribution in development, healing, aging, and disease.
Feugere, Lauric; Silva De Freitas, Claudio; Bates, Adam; Storey, Kenneth B.; Beltran‐Alvarez, Pedro; Wollenberg Valero, Katharina C.
doi: 10.1002/1873-3468.70047pmid: 40265659
Since stress can be transmitted to congeners via social metabolites, it is paramount to understand how the social context of abiotic stress influences aquatic organisms' responses to global changes. Here, we integrated the transcriptomic and phenotypic responses of zebrafish embryos to a UV damage/repair assay following scenarios of heat stress, its social context and their combination. Heat stress preceding UV exposure had a hormetic effect through the cellular stress response and DNA repair, rescuing and/or protecting embryos from UV damage. However, experiencing heat stress within a social context negated this molecular hormetic effect and lowered larval fitness. We discuss the molecular basis of interindividual chemical transmission within animal groups as another layer of complexity to organisms' responses to environmental stressors.
Fierro, Ludivine; Ishii, Anna; Aoyama, Haruka; Arae, Toshihiro; Chiba, Yukako; Kotani, Tomoya
doi: 10.1002/1873-3468.70106pmid: 40598765
Eggs accumulate more than 10 000 mRNAs, from which proteins are synthesized constitutively or in a temporally controlled manner. Although changes in the translation state of these mRNAs are crucial for early development, how embryos orchestrate them remains unclear. Here, we investigated changes in mRNA 3′ untranslated regions (UTRs) using 3′ end‐RNA sequencing of zebrafish embryos and computational methods. Consistent with our previous finding that pou5f3 mRNA is shortened at the 3′UTR during early development, thousands of mRNAs showed shortening of the 3′UTRs. Moreover, we found that most mRNAs in embryos contained several different 3′ ends and their proportion was dynamically changed. These changes were coupled with protein synthesis. Our results reveal genome‐wide 3′‐end dynamics in the regulation of biological processes.
Wang, Beibei; Cui, Mengge; Liu, Huan; Sui, Ming; Wu, Xueyan; Liu, Yu; Zhang, Bin
doi: 10.1002/1873-3468.70050pmid: 40290048
The neuromuscular junction (NMJ) performs the crucial function of controlling skeletal muscle contraction. NMJ formation depends on the Agrin/Lrp4/MuSK/Dok‐7 signaling pathway. However, signaling downstream of Dok‐7 remains incompletely understood. Here we used the phosphorylated iTRAQ technique to identify downstream molecules of Dok‐7 in muscle cells. We found 16 Agrin/Dok‐7‐mediated serine/threonine phosphorylated proteins, and we validated the role of one phosphorylated protein, JPH2, in regulating AChR clustering. Our phosphoproteomics analysis sheds light on the underappreciated signaling network downstream of Agrin/Dok‐7, thus providing new clues for understanding pathogenesis and developing treatment methods for neuromuscular diseases.
Jiang, Muwei; Bianchi, Frans; Bogaart, Geert
doi: 10.1002/1873-3468.70064pmid: 40325954
Short‐chain fatty acids (SCFAs), produced by dietary fiber fermentation in the colon, play essential roles in cellular metabolism, with butyrate notably modulating immune responses and epigenetic regulation. Their production contributes to an acidic colonic environment where protonated SCFAs permeate membranes, leading to intracellular acidification and SCFA accumulation. Using our method to measure intracellular pH, we investigated how extracellular pH influences butyrate‐induced acidification and immunomodulatory effects in human macrophages. Our data show that butyrate accumulates and acidifies cells at acidic extracellular pH due to the permeability of its protonated form. While inflammatory cytokine production was mildly influenced by extracellular pH, butyrate‐induced histone acetylation exhibited a pH dependence, underscoring the importance of considering extracellular pH when assessing the SCFA's functions.
Busche, Roger; Riordan, John R.; Tümmler, Burkhard
doi: 10.1002/1873-3468.70083pmid: 40448544
Cryo‐electron microscopy has yielded high‐resolution structural data of the multidrug efflux transporter P‐glycoprotein (ABCB1), but its direct and indirect interactions within the native membrane environment have remained largely unexplored. Here, we compared the fluidity gradients of plasma membranes of the drug‐sensitive CHO cell line AuxB1 and its P‐glycoprotein overexpressing derivative B30 by fluorescence anisotropy of embedded n‐(9‐anthroyloxy) fatty acid probes (n = 2, 7, 9, 12, 16) in the temperature range of 10–50 °C. The shape of the temperature profiles of probe mobility was comparable in AuxB1 and B30 membranes, but did not match. Overexpression of P‐glycoprotein smoothened the transversal gradient of the out‐of‐plane mode of rotation of the probes, which may facilitate the partitioning of hydrophobic drugs into the membrane and thereby increase the speed of P‐glycoprotein to pump the drug out of the cell.
Romp, Erik; Rataj, Katharina; König, Stefanie; Newcomer, Marcia E.; Werz, Oliver; Garscha, Ulrike
doi: 10.1002/1873-3468.70066pmid: 40344218
Leukotrienes, synthesized via the 5‐lipoxygenase (5‐LOX) pathway in the arachidonic acid cascade, are critical in inflammation. Effective leukotriene production requires interaction between 5‐LOX and 5‐LOX‐activating protein (FLAP) at the nuclear membrane. This study used site‐directed mutagenesis to explore amino acid residues in FLAP's inhibitor binding pocket and cytosolic loops, assessing their impact on 5‐LOX product formation, the FLAP inhibitor MK886's efficacy, 5‐LOX translocation, and 5‐LOX/FLAP complex formation. Mutations in the second cytosolic loop, especially at residue S108, reduced MK886 potency and disrupted 5‐LOX/FLAP complex formation. These results highlight the second cytosolic loop of FLAP in the 5‐LOX/FLAP interaction and proper leukotriene formation and suggest that targeting this region could aid in the development of new FLAP inhibitors with improved pharmacokinetics.
Borg, Annika J. E.; De Cnop, Laura; Nidetzky, Bernd
doi: 10.1002/1873-3468.70070pmid: 40377033
UDP‐glucuronic acid 4‐epimerase (UGAepi) catalyzes the NAD+‐dependent interconversion of UDP‐glucuronic acid (UDP‐GlcA) and UDP‐galacturonic acid (UDP‐GalA) through a mechanism involving C4‐oxidation, 4‐keto‐intermediate rotation, and subsequent reduction. Here, the functional significance of the substrate's carboxylate group in the epimerization process was investigated using UDP‐4‐keto‐pentose, an analogous intermediate that lacks a carboxylate moiety. Site‐directed mutations were introduced into UGAepi from Bacillus cereus (BcUGAepi) to increase substrate binding pocket flexibility, enabling the variant enzymes to accommodate UDP‐4‐keto‐pentose more efficiently than the wild‐type does. Although these BcUGAepi variants partially maintained nonstereospecific C4‐epimerization activity with UDP‐GlcA, they demonstrated fully stereospecific reduction of UDP‐4‐keto‐pentose to UDP‐xylose. These findings highlight the critical role of the carboxylate moiety as an essential element for epimerization in BcUGAepi, and elucidate the structural determinants of substrate specificity in UGAepis.
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