The Aspergillus fumigatus growth determinant Afu6g07200 is the first granulin described in fungi

The Aspergillus fumigatus growth determinant Afu6g07200 is the first granulin described in fungi | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Aspergillus fumigatus growth determinant Afu6g07200 is the first granulin described in fungi Uxue Perez-Cuesta, Xabier Guruceaga, Eduardo Pelegri-Martinez, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9044607/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The Granulin motif is an ancient extracellular growth determinant in eukaryotes but not in fungi. The motif consists of 12 cysteines that give the protein a unique tertiary structure of four stacked β-hairpins. In humans, this domain is related to survival, growth modulation, migration, inflammation, wound repair, and diseases like frontotemporal dementia, Alzheimer's disease, and cancer. The protein encoded by the gene Afu6g07200 of Aspergillus fumigatus shows a domain with predicted granulin structure and is overexpressed during spore germination. Despite low conservation of its amino acid sequence, this domain exhibits the same predicted 3D structure as several human granulins, with the highest confidence (95.4%) being observed with human GRNA. Moreover, this protein is conserved among the Pezizomycotina subdivision. In this study, we demonstrate that this A. fumigatus protein is involved in proliferation, polarization, cell wall integrity, cytoskeletal organization, stress response, and sensing. Fungal granulin is implicated in maintaining the periplasmic space, is related to polarity markers and actin, and plays an essential role in activating MAPK cascades. Furthermore, complementation with human GRNA fulfilled the activities of the fungal protein at morphological and molecular levels. Therefore, this is the first description of a granulin domain in filamentous fungi based on 3D structure and function homology. Biological sciences/Microbiology/Pathogens Biological sciences/Microbiology/Fungi/Fungal biology Biological sciences/Microbiology/Fungi/Fungal genetics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files FigureS1.pdf FigureS1. Proliferation analysis. A) Colonial diameter measurement growing in RPMI-Agar B) Microdilution spots growing at different temperatures and pHs. All the experiments were done in triplicate, and data are presented as mean ±SD. *p<0.033 p<0.002 * p<0.0002 p<0.0001 figureS2.pdf Figure S2. Chitin content visualization by CFW staining with the corresponding histograms. FigureS3.pdf Figure S3. Antifungal resistance. A) Caspofungin E-test assay. Colonial diameter measurement in contact with B)Caspofungin or C) Nikkomicyn Z. Three biological replicates were assessed, and data are presented as mean ±SD. *p<0.033, **p<0.002, ***p<0.0002, ****p<0.0001. FigureS4.pdf Figure S4. Response to PGRN treatment. A) Exogenous treatment with PGRN for 24 hours. Arrows indicate swollen tips and conidia B) Conidial diameter measurement with and without PGRN treatment C) Immunodetection of PGRN hydrolysis in contact with A. fumigatus for 24 hours, compared to the positive control and PGRN incubated at the same conditions as with the fungi. figureS5.pdf Figure S5. In vitro and in vivo effect of grn gene. A-B)Phagocytosis assay of the co-incubation of RAW 264.7 cell line and fungal strains. C) Germination, D) Double axis emergence, and E)Early hyphal branches percentage of strains growing alone or in co-incubation with macrophages for 8 hours. At least three biological replicates were assessed, and data are presented as mean ±SD. F)Kaplan-Meier analysis of neutropenic infected mice during 15 days post intranasal exposition to Wt, Δgrn , and Δgrn::grn strains (n=20). G) Histology of pulmonary parenchyma after 2 days post-infection (Hyphae in black). H)Hyphae in lung parenchyma (red arrows) and venous vessels (blue arrows). I)Histology of pulmonary parenchyma after 1 day post-infection with Δgrn strain.*p<0.033, **p<0.002, ***p<0.0002, ****p<0.0001. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9044607","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":609518460,"identity":"8b76496f-14c2-45fb-a2b6-d7022971917c","order_by":0,"name":"Uxue Perez-Cuesta","email":"","orcid":"","institution":"Department of Clinical Pharmacy and Translational Science, Pharmacy College, UTHSC, Memphis, Tennessee, USA","correspondingAuthor":false,"prefix":"","firstName":"Uxue","middleName":"","lastName":"Perez-Cuesta","suffix":""},{"id":609518459,"identity":"8ec08293-e4a4-4ce9-842c-d7d0829bcc4d","order_by":1,"name":"Xabier Guruceaga","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3258-2482","institution":"Institute for Multidisciplinary Research in Applied Biology (IMAB), Public University of Navarre (UPNA), Campus de Arrosadia, Pamplona, Spain","correspondingAuthor":true,"prefix":"","firstName":"Xabier","middleName":"","lastName":"Guruceaga","suffix":""},{"id":609518461,"identity":"c3f556f5-b40d-4890-8466-119902830236","order_by":2,"name":"Eduardo Pelegri-Martinez","email":"","orcid":"https://orcid.org/0000-0001-6512-7772","institution":"Department of Immunology, Microbiology and Parasitology, University of Basque Country (UPV/EHU), Leioa, Spain","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"","lastName":"Pelegri-Martinez","suffix":""},{"id":609518462,"identity":"46729fe3-4349-4bc4-917c-7400b7bc53e8","order_by":3,"name":"Saioa Cendon-Sanchez","email":"","orcid":"https://orcid.org/0000-0001-6712-6941","institution":"Department of Immunology, Microbiology and Parasitology, University of Basque Country (UPV/EHU), Leioa, Spain","correspondingAuthor":false,"prefix":"","firstName":"Saioa","middleName":"","lastName":"Cendon-Sanchez","suffix":""},{"id":609518463,"identity":"17b4717d-e7ed-478e-91b0-9689e72a7a31","order_by":4,"name":"Adela Martin-Vicente","email":"","orcid":"","institution":"Department of Clinical Pharmacy and Translational Science, Pharmacy College, UTHSC, Memphis, Tennessee, USA","correspondingAuthor":false,"prefix":"","firstName":"Adela","middleName":"","lastName":"Martin-Vicente","suffix":""},{"id":609518464,"identity":"d8e27bef-d5db-4a86-80e9-4066020434b0","order_by":5,"name":"Harrison Thorn","email":"","orcid":"https://orcid.org/0009-0003-2546-8400","institution":"Department of Clinical Pharmacy and Translational Science, Pharmacy College, UTHSC, Memphis, Tennessee, USA; 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All the experiments were done in triplicate, and data are presented as mean ±SD. *p\u0026lt;0.033**p\u0026lt;0.002 ***p\u0026lt;0.0002****p\u0026lt;0.0001\u003c/p\u003e","description":"","filename":"FigureS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9044607/v1/904bed8ab35963852c9b0e28.pdf"},{"id":105177241,"identity":"34f5f01d-e640-4f81-b3cc-b331a439f840","added_by":"auto","created_at":"2026-03-23 06:20:25","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":26868002,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S2.\u003c/strong\u003e Chitin content visualization by CFW staining with the corresponding histograms.\u003c/p\u003e","description":"","filename":"figureS2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9044607/v1/e6f310a977bbc48f8b39131e.pdf"},{"id":105177244,"identity":"aef008ab-6236-4143-bb32-1cd74ff4aa1c","added_by":"auto","created_at":"2026-03-23 06:20:25","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":95404306,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S3\u003c/strong\u003e. Antifungal resistance. \u003cstrong\u003eA)\u003c/strong\u003e Caspofungin E-test assay. Colonial diameter measurement in contact with \u003cstrong\u003eB)\u003c/strong\u003eCaspofungin or \u003cstrong\u003eC)\u003c/strong\u003e Nikkomicyn Z. Three biological replicates were assessed, and data are presented as mean ±SD. *p\u0026lt;0.033, **p\u0026lt;0.002, ***p\u0026lt;0.0002, ****p\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"FigureS3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9044607/v1/f3b6dcafba579a5c29c79d2f.pdf"},{"id":105177242,"identity":"592e727c-084c-4b91-9c1c-ea7bf4dcc0ad","added_by":"auto","created_at":"2026-03-23 06:20:25","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":91169685,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S4.\u003c/strong\u003e Response to PGRN treatment. \u003cstrong\u003eA)\u003c/strong\u003e Exogenous treatment with PGRN for 24 hours. Arrows indicate swollen tips and conidia \u003cstrong\u003eB)\u003c/strong\u003e Conidial diameter measurement with and without PGRN treatment \u003cstrong\u003eC)\u003c/strong\u003e Immunodetection of PGRN hydrolysis in contact with \u003cem\u003eA. fumigatus \u003c/em\u003efor 24 hours,\u003cem\u003e \u003c/em\u003ecompared to the positive control and PGRN incubated at the same conditions as with the fungi.\u003c/p\u003e","description":"","filename":"FigureS4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9044607/v1/057c86e6cc6616b98a4f1c5e.pdf"},{"id":105177245,"identity":"4d421c3d-0a75-4f65-8bf7-d56cde701e62","added_by":"auto","created_at":"2026-03-23 06:20:26","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":21881251,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S5.\u003c/strong\u003e \u003cem\u003eIn vitro \u003c/em\u003eand \u003cem\u003ein vivo\u003c/em\u003e effect of \u003cem\u003egrn\u003c/em\u003e gene. \u003cstrong\u003eA-B)\u003c/strong\u003ePhagocytosis assay of the co-incubation of RAW 264.7 cell line and fungal strains. \u003cstrong\u003eC)\u003c/strong\u003e Germination, \u003cstrong\u003eD\u003c/strong\u003e) Double axis emergence, and\u003cstrong\u003e E)\u003c/strong\u003eEarly hyphal branches percentage of strains growing alone or in co-incubation with macrophages for 8 hours. At least three biological replicates were assessed, and data are presented as mean ±SD. \u003cstrong\u003eF)\u003c/strong\u003eKaplan-Meier analysis of neutropenic infected mice during 15 days post intranasal exposition to Wt, \u003cem\u003eΔgrn\u003c/em\u003e, and \u003cem\u003eΔgrn::grn\u003c/em\u003e strains (n=20). \u003cstrong\u003eG)\u003c/strong\u003e Histology of pulmonary parenchyma after 2 days post-infection (Hyphae in black). \u003cstrong\u003eH)\u003c/strong\u003eHyphae in lung parenchyma (red arrows) and venous vessels (blue arrows). \u003cstrong\u003eI)\u003c/strong\u003eHistology of pulmonary parenchyma after 1 day post-infection with \u003cem\u003eΔgrn\u003c/em\u003e strain.*p\u0026lt;0.033, **p\u0026lt;0.002, ***p\u0026lt;0.0002, ****p\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"figureS5.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9044607/v1/d58b1e666daf94a1ccec2a49.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"The Aspergillus fumigatus growth determinant Afu6g07200 is the first granulin described in fungi","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9044607/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9044607/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The Granulin motif is an ancient extracellular growth determinant in eukaryotes but not in fungi. The motif consists of 12 cysteines that give the protein a unique tertiary structure of four stacked β-hairpins. In humans, this domain is related to survival, growth modulation, migration, inflammation, wound repair, and diseases like frontotemporal dementia, Alzheimer's disease, and cancer. The protein encoded by the gene Afu6g07200 of Aspergillus fumigatus shows a domain with predicted granulin structure and is overexpressed during spore germination. Despite low conservation of its amino acid sequence, this domain exhibits the same predicted 3D structure as several human granulins, with the highest confidence (95.4%) being observed with human GRNA. Moreover, this protein is conserved among the Pezizomycotina subdivision. In this study, we demonstrate that this A. fumigatus protein is involved in proliferation, polarization, cell wall integrity, cytoskeletal organization, stress response, and sensing. Fungal granulin is implicated in maintaining the periplasmic space, is related to polarity markers and actin, and plays an essential role in activating MAPK cascades. Furthermore, complementation with human GRNA fulfilled the activities of the fungal protein at morphological and molecular levels. Therefore, this is the first description of a granulin domain in filamentous fungi based on 3D structure and function homology.","manuscriptTitle":"The Aspergillus fumigatus growth determinant Afu6g07200 is the first granulin described in fungi","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-23 06:20:19","doi":"10.21203/rs.3.rs-9044607/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1617db6a-2250-4cf5-ace5-f71ba80398b6","owner":[],"postedDate":"March 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":64859517,"name":"Biological sciences/Microbiology/Pathogens"},{"id":64859518,"name":"Biological sciences/Microbiology/Fungi/Fungal biology"},{"id":64859519,"name":"Biological sciences/Microbiology/Fungi/Fungal genetics"}],"tags":[],"updatedAt":"2026-04-15T10:18:57+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-23 06:20:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9044607","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9044607","identity":"rs-9044607","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}