FASEB bioAdvances最新文献

{"title":"Club cell-specific telomere protection protein 1 (TPP1) protects against tobacco smoke-induced lung inflammation, xenobiotic metabolic dysregulation, and injurious responses","authors":"Thivanka Muthumalage,&nbsp;Chiara Goracci,&nbsp;Irfan Rahman","doi":"10.1096/fba.2023-00115","DOIUrl":"10.1096/fba.2023-00115","url":null,"abstract":"<p>Inhaling xenobiotics, such as tobacco smoke is a major risk factor for pulmonary diseases, e.g., COPD/emphysema, interstitial lung disease, and pre-invasive diseases. Shelterin complex or telosome provides telomeric end protection during replication. Telomere protection protein 1 (TPP1) is one of the main six subunits of the shelterin complex supporting the telomere stability and genomic integrity. Dysfunctional telomeres and shelterin complex are associated as a disease mechanism of tobacco smoke-induced pulmonary damage and disease processes. The airway epithelium is critical to maintaining respiratory homeostasis and is implicated in lung diseases. Club cells (also known as clara cells) play an essential role in the immune response, surfactant production, and metabolism. Disrupted shelterin complex may lead to dysregulated cellular function, DNA damage, and disease progression. However, it is unknown if the conditional removal of TPP1 from Club cells can induce lung disease pathogenesis caused by tobacco smoke exposure. In this study, conditional knockout of Club-cell specific TPP1 demonstrated the instability of other shelterin protein subunits, such as TRF1, dysregulation of cell cycle checkpoint proteins, p53 and downstream targets, and dysregulation of telomeric genes. This was associated with age-dependent senescence-associated genes, increased DNA damage, and upregulated RANTES/IL13/IL33 mediated lung inflammation and injury network by cigarette smoke (CS). These phenomena are also associated with alterations in cytochrome P450 and glutathione transferases, upregulated molecular pathways promoting lung lesions, bronchial neoplasms, and adenocarcinomas. These findings suggest a pivotal role of TPP1 in maintaining lung homeostasis and injurious responses in response to CS. Thus, these data TPP1 may have therapeutic value in alleviating telomere-related chronic lung diseases.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 2","pages":"53-71"},"PeriodicalIF":2.7,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139622618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of air–liquid interface on cultured human intestinal epithelial cells","authors":"Akanksha Sabapaty,&nbsp;Po-Yu Lin,&nbsp;James C. Y. Dunn","doi":"10.1096/fba.2023-00132","DOIUrl":"10.1096/fba.2023-00132","url":null,"abstract":"<p>The intestinal epithelium is a dynamic barrier that allows the selective exchange of ions, hormones, proteins, and nutrients. To accomplish this, the intestinal epithelium adopts a highly columnar morphology which is partially lost in submerged culturing systems. To achieve this, small intestinal tissue samples were utilized to obtain human intestinal crypts to form enteroids. The Transwell system was subsequently employed to form a monolayer of cells that was cultured in either the submerged condition or the air–liquid Interface (ALI) condition. We found that the human intestinal monolayer under the ALI condition exhibited morphology more similar to the normal intestinal epithelium. F-actin localization and brush border formation were observed apically, and the integrity of the tight junctions was preserved in the ALI condition. Fewer apoptotic cells were observed in the ALI conditions as compared to the submerged conditions. The monolayer of cells expressed a higher level of secretory cell lineage genes in the ALI condition. The ALI condition positively contributes toward a more differentiated phenotype of epithelial cells. It serves as an amplifier that enhances the existing differentiation cue. The ALI system provides a more differentiated platform to study intestinal function compared to submerged conditions.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 2","pages":"41-52"},"PeriodicalIF":2.7,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138952490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered microheterogeneity at several N-glycosylation sites in OPSCC in constant protein expression conditions","authors":"Amy Dickinson,&nbsp;Sakari Joenväärä,&nbsp;Tiialotta Tohmola,&nbsp;Jutta Renkonen,&nbsp;Petri Mattila,&nbsp;Timo Carpén,&nbsp;Antti Mäkitie,&nbsp;Suvi Silén","doi":"10.1096/fba.2023-00066","DOIUrl":"10.1096/fba.2023-00066","url":null,"abstract":"<p>Protein glycosylation responds sensitively to disease states. It is implicated in every hallmark of cancer and has recently started to be considered as a hallmark itself. Changes in N-glycosylation microheterogeneity are more dramatic than those of protein expression due to the non-template nature of protein glycosylation. This enables their potential use in serum-based diagnostics. Here, we perform glycopeptidomics on serum from patients with oropharyngeal squamous cell carcinoma (OPSCC), compared to controls and comparing between cancers based on etiology (human papilloma virus- positive or negative). Using MS2, we then targeted glycoforms, significantly different between the groups, to identify their glycopeptide compositions. Simultaneously we investigate the same serum proteins, comparing whether N-glycosylation changes reflect protein-level changes. Significant glycoforms were identified from proteins such as alpha-1-antitrypsin (SERPINA1), haptoglobin, and different immunoglobulins. SERPINA1 had glycovariance at 2 N-glycosylation sites, that were up to 35 times more abundant in even early-stage OPSCCs, despite minimal differences between SERPINA1 protein levels between groups. Some identified glycoforms' fold changes (FCs) were in line with serum protein level FCs, others were less abundant in early-stage cancers but with great variance in higher-stage cancers, such as on immunoglobulin heavy constant gamma 2, despite no change in protein levels. Such findings indicate that glycovariant analysis might be more beneficial than proteomic analysis, which is yet to be fruitful in the search for biomarkers. Highly sensitive glycopeptide changes could potentially be used in the future for cancer screening. Additionally, characterizing the glycopeptide changes in OPSCC is valuable in the search for potential therapeutic targets.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 1","pages":"26-39"},"PeriodicalIF":2.7,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138974648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to “From goal to outcome: Analyzing the progression of biomedical sciences PhD careers in a longitudinal study using an expanded taxonomy”","authors":"","doi":"10.1096/fba.2023-00134","DOIUrl":"10.1096/fba.2023-00134","url":null,"abstract":"<p>Brown, A. M., Meyers, L. C., Varadarajan, J., Ward, N. J., Cartailler, J. P., Chalkley, R. G., Gould, K. L., and Petrie, K. A. From goal to outcome: Analyzing the progression of biomedical sciences PhD careers in a longitudinal study using an expanded taxonomy. <i>FASEB BioAdvances</i> 2023;5:427–452. https://doi.org/10.1096/fba.2023-00072</p><p>This article is part of the Bioscience Careers special collection. It was added to the collection after publication.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 1","pages":"40"},"PeriodicalIF":2.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138626074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toll-interacting protein inhibits transforming growth factor beta signaling in mouse lung fibroblasts","authors":"Yu-Hua Chow,&nbsp;Cecilia López-Martínez,&nbsp;W. Conrad Liles,&nbsp;William A. Altemeier,&nbsp;Sina A. Gharib,&nbsp;Chi F. Hung","doi":"10.1096/fba.2023-00054","DOIUrl":"10.1096/fba.2023-00054","url":null,"abstract":"<p>Variations in the Toll-interacting protein (TOLLIP) gene have been identified in genome-wide association studies to correlate with risk of disease, mortality, and response to N-acetylcysteine therapy in idiopathic pulmonary fibrosis. Although TOLLIP is known to modulate innate immune responses, its relevance in organ fibrogenesis remains unknown. Prior work in the literature suggests TOLLIP dampens transforming growth factor beta (TGFβ) signaling in human cell lines. In this study, we examined the role of TOLLIP in mouse lung fibroblast (MLF) responses to TGFβ and in the bleomycin model of experimental lung fibrosis using <i>Tollip−/−</i> mice. We hypothesize that if TOLLIP negatively regulates TGFβ signaling, then <i>Tollip−/−</i> mouse lung fibroblasts (MLFs) would have enhanced response to TGFβ treatment, and <i>Tollip−/−</i> mice would develop increased fibrosis following bleomycin challenge. Primary MLFs were stimulated with TGFβ (1 ng/mL) for 24 h. RNA was obtained to assess global transcriptional responses by RNA-seq and markers of myofibroblast transition by qPCR. Functional assessment of TGFβ-stimulated MLFs included cell migration by scratch assay, cell proliferation, and matrix invasion through Matrigel. In the in vivo model of lung fibrosis, <i>Tollip−/−</i> mice and wild-type (WT) littermates were administered bleomycin intratracheally and assessed for fibrosis. We further examined TGFβ signaling in vivo after bleomycin injury by SMAD2, ERK1/2, and TGFβR1 Western blot. In response to TGFβ treatment, both WT and <i>Tollip−/−</i> MLFs exhibited global transcriptional changes consistent with myofibroblast differentiation. However, <i>Tollip−/−</i> MLFs showed greater number of differentially expressed genes compared to WT MLFs and greater upregulation of <i>Acta2</i> by qPCR. Functionally, <i>Tollip−/−</i> MLFs also exhibited increased migration and Matrigel invasiveness compared to WT. We found evidence of enhanced TGFβ signaling in <i>Tollip−/−</i> through SMAD2 in vitro and in vivo. <i>Tollip−/−</i> mice experienced lower survival using a standard weight-adjusted dosing without evidence of differences in fibrosis at Day 21. With adjustment of dosing for sex, no differences were observed in fibrosis at Day 21. However, <i>Tollip−/−</i> mice had greater weight loss and increased bronchoalveolar lavage fluid total protein during early resolution at Day 14 compared to WT without evidence of differences in acute lung injury at Day 7, suggesting impaired resolution of lung injury.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 1","pages":"12-25"},"PeriodicalIF":2.7,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139211308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mustn1 ablation in skeletal muscle results in functional alterations","authors":"Charles J. Kim,&nbsp;Chanpreet Singh,&nbsp;Marina Kaczmarek,&nbsp;Madison O'Donnell,&nbsp;Christine Lee,&nbsp;Kevin DiMagno,&nbsp;Melody W. Young,&nbsp;William Letsou,&nbsp;Raddy L. Ramos,&nbsp;Michael C. Granatosky,&nbsp;Michael Hadjiargyrou","doi":"10.1096/fba.2023-00082","DOIUrl":"https://doi.org/10.1096/fba.2023-00082","url":null,"abstract":"<p><i>Mustn1</i>, a gene expressed exclusively in the musculoskeletal system, was shown in previous in vitro studies to be a key regulator of myogenic differentiation and myofusion. Other studies also showed <i>Mustn1</i> expression associated with skeletal muscle development and hypertrophy. However, its specific role in skeletal muscle function remains unclear. This study sought to investigate the effects of <i>Mustn1</i> in a conditional knockout (KO) mouse model in Pax7 positive skeletal muscle satellite cells. Specifically, we investigated the potential effects of <i>Mustn1</i> on myogenic gene expression, grip strength, alterations in gait, ex vivo investigations of isolated skeletal muscle isometric contractions, and potential changes in the composition of muscle fiber types. Results indicate that <i>Mustn1</i> KO mice did not present any substantial phenotypic changes or significant variations in genes related to myogenic differentiation and fusion. However, an approximately 10% decrease in overall grip strength was observed in the 2-month-old KO mice in comparison to the control wild type (WT), but this decrease was not significant when normalized by weight. KO mice also generated approximately 8% higher vertical force than WT at 4 months in the hindlimb. Ex vivo experiments revealed decreases in about 20 to 50% in skeletal muscle contractions and about 10%–20% fatigue in soleus of both 2- and 4-month-old KO mice, respectively. Lastly, immunofluorescent analyses showed a persistent increase of Type IIb fibers up to 15-fold in the KO mice while Type I fibers decreased about 20% and 30% at both 2 and 4 months, respectively. These findings suggest a potential adaptive or compensatory mechanism following <i>Mustn1</i> loss, as well as hinting at an association between <i>Mustn1</i> and muscle fiber typing. Collectively, <i>Mustn1</i>'s complex roles in skeletal muscle physiology requires further research, particularly in terms of understanding the potential role of <i>Mustn1</i> in muscle repair and regeneration, as well as with influence of exercise. Collectively, these will offer valuable insights into <i>Mustn1</i>'s key biological functions and regulatory pathways.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 12","pages":"541-557"},"PeriodicalIF":2.7,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138571072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling","authors":"Elena Silva,&nbsp;Véronique Ferchaud-Roucher,&nbsp;Anita Kramer,&nbsp;Lana Madi,&nbsp;Priyadarshini Pantham,&nbsp;Stephanie Chassen,&nbsp;Thomas Jansson,&nbsp;Theresa L. Powell","doi":"10.1096/fba.2023-00113","DOIUrl":"10.1096/fba.2023-00113","url":null,"abstract":"<p>Normal fetal development is critically dependent on optimal nutrient supply by the placenta, and placental amino acid transport has been demonstrated to be positively associated with fetal growth. Mechanistic target of rapamycin (mTOR) is a positive regulator of placental amino acid transporters, such as System A. Oleic acid (OA) has been previously shown to have a stimulatory role on placental mTOR signaling and System A amino acid uptake in primary human trophoblast (PHT) cells. We investigated the mechanistic link between OA and System A activity in PHT. We found that inhibition of mTOR complex 1 or 2, using small interfering RNA to knock down raptor or rictor, prevented OA-stimulated System A amino acid transport indicating the interaction of OA with mTOR. Phosphatidic acid (PA) is a key intermediary for phospholipid biosynthesis and a known regulator of the mTOR pathway; however, phospholipid biosynthetic pathways have not been extensively studied in placenta. We identified placental isoforms of acyl transferase enzymes involved in de novo phospholipid synthesis. Silencing of 1-acylglycerol-3-phosphate-O-acyltransferase-4, an enzyme in this pathway, prevented OA mediated stimulation of mTOR and System A amino acid transport. These data indicate that OA stimulates mTOR and amino acid transport in PHT cells mediated through de novo synthesis of PA. We speculate that fatty acids in the maternal circulation, such as OA, regulate placental functions critical for fetal growth by interaction with mTOR and that late pregnancy hyperlipidemia may be critical for increasing nutrient transfer to the fetus.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 1","pages":"1-11"},"PeriodicalIF":2.7,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased lethality of respiratory infection by Streptococcus pneumoniae in the Dp16 mouse model of Down syndrome","authors":"Kelley L. Colvin,&nbsp;Robert J. Elliott,&nbsp;Desiree M. Goodman,&nbsp;Julie Harral,&nbsp;Edward G. Barrett,&nbsp;Michael E. Yeager","doi":"10.1096/fba.2023-00091","DOIUrl":"10.1096/fba.2023-00091","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We sought to investigate whether the Dp16 mouse model of Down syndrome (DS) is more susceptible to severe and lethal respiratory tract infection by <i>Streptococcus pneumoniae</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Study Design</h3>\u0000 \u0000 <p>We infected controls and Dp16 mice with <i>Streptococcus pneumoniae</i> and measured survival rates. We compared cytokine production by primary lung cell cultures exposed to <i>Streptococcus pneumoniae</i>. We examined lung protein expression for interferon signaling related pathways. We characterized the histopathology and quantified the extent of bronchus-associated lymphoid tissue. Finally, we examined mouse tissues for the presence of oligomeric tau protein.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the Dp16 mouse model of DS displayed significantly higher susceptibility to lethal respiratory infection with <i>Streptococcus pneumoniae</i> compared to control mice. Lung cells cultured from Dp16 mice displayed unique secreted cytokine profiles compared to control mice. The Dp16 mouse lungs were characterized by profound lobar pneumonia with massive diffuse consolidation involving nearly the entire lobe. Marked red hepatization was noted, and Dp16 mice lungs contained numerous bronchus-associated lymphoid tissues that were highly follicularized. Compared to uninfected mice, both control mice and Dp16 mice infected with <i>Streptococcus pneumoniae</i> showed evidence of oligomeric tau aggregates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Increased susceptibility to severe respiratory tract infection with <i>Streptococcus pneumoniae</i> in Dp16 mice closely phenocopies infection in individuals with DS. The increase does not appear to be linked to overexpression of mouse interferon genes syntenic to human chromosome 21.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 12","pages":"528-540"},"PeriodicalIF":2.7,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136104382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidants restore store-operated Ca2+ entry in patient-iPSC-derived myotubes with tubular aggregate myopathy-associated Ile484ArgfsX21 STIM1 mutation via upregulation of binding immunoglobulin protein","authors":"Fusako Sakai-Takemura,&nbsp;Fumiaki Saito,&nbsp;Ken'ichiro Nogami,&nbsp;Yusuke Maruyama,&nbsp;Ahmed Elhussieny,&nbsp;Kiichiro Matsumura,&nbsp;Shin'ichi Takeda,&nbsp;Yoshitsugu Aoki,&nbsp;Yuko Miyagoe-Suzuki","doi":"10.1096/fba.2023-00069","DOIUrl":"https://doi.org/10.1096/fba.2023-00069","url":null,"abstract":"<p>Store-operated Ca²⁺ entry (SOCE) is indispensable for intracellular Ca²⁺ homeostasis in skeletal muscle, and constitutive activation of SOCE causes tubular aggregate myopathy (TAM). To understand the pathogenesis of TAM, we induced pluripotent stem cells (iPSCs) from a TAM patient with a rare mutation (c.1450_1451insGA; p. Ile484ArgfsX21) in the <i>STIM1</i> gene. This frameshift mutation produces a truncated STIM1 with a disrupted C-terminal inhibitory domain (CTID) and was reported to diminish SOCE. Myotubes induced from the patient's-iPSCs (TAM myotubes) showed severely impaired SOCE, but antioxidants greatly restored SOCE partly via upregulation of an endoplasmic reticulum (ER) chaperone, BiP (GRP78), in the TAM myotubes. Our observation suggests that antioxidants are promising tools for treatment of TAM caused by reduced SOCE.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 11","pages":"453-469"},"PeriodicalIF":2.7,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71982294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human wild-type and D76N β2-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans","authors":"Sara Raimondi,&nbsp;Giulia Faravelli,&nbsp;Paola Nocerino,&nbsp;Valentina Mondani,&nbsp;Alma Baruffaldi,&nbsp;Loredana Marchese,&nbsp;Maria Chiara Mimmi,&nbsp;Diana Canetti,&nbsp;Guglielmo Verona,&nbsp;Marianna Caterino,&nbsp;Margherita Ruoppolo,&nbsp;P. Patrizia Mangione,&nbsp;Vittorio Bellotti,&nbsp;Francesca Lavatelli,&nbsp;Sofia Giorgetti","doi":"10.1096/fba.2023-00073","DOIUrl":"https://doi.org/10.1096/fba.2023-00073","url":null,"abstract":"<p>β₂-microglobulin (β₂-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β₂-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (<i>C. elegans</i>) strain expressing human WT β₂-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N β₂-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β₂-m levels rather than with the presence of mutations, being more pronounced in WT β₂-m worms. β₂-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT β₂-m at high concentration compared to D76N β₂-m worms. Altogether, these data show that β₂-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary β₂-m amyloidosis (high levels of non-mutated β₂-m vs. normal levels of variant β₂-m) and provide important clues on the molecular bases of these human diseases.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 11","pages":"484-505"},"PeriodicalIF":2.7,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72001853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}