{"id":26261,"date":"2023-11-30T09:44:23","date_gmt":"2023-11-30T07:44:23","guid":{"rendered":"https:\/\/medri.uniri.hr\/?page_id=26261"},"modified":"2024-08-22T15:55:48","modified_gmt":"2024-08-22T13:55:48","slug":"role-of-arf-gtpases-in-pathogenesis-of-citomegalovirus-infection-arf-cmv","status":"publish","type":"page","link":"https:\/\/medri.uniri.hr\/en\/projects\/role-of-arf-gtpases-in-pathogenesis-of-citomegalovirus-infection-arf-cmv\/","title":{"rendered":"Role of Arf GTPases in pathogenesis of citomegalovirus infection (Arf &amp; CMV)\u00a0"},"content":{"rendered":"\n<figure class=\"wp-block-image size-full is-resized\"><a href=\"https:\/\/medri.uniri.hr\/wp-content\/uploads\/2024\/02\/image-1.png\"><img fetchpriority=\"high\" decoding=\"async\" width=\"570\" height=\"269\" src=\"https:\/\/medri.uniri.hr\/wp-content\/uploads\/2024\/02\/image-1.png\" alt=\"\" class=\"wp-image-22218\" style=\"width:403px;height:auto\" srcset=\"https:\/\/medri.uniri.hr\/wp-content\/uploads\/2024\/02\/image-1.png 570w, https:\/\/medri.uniri.hr\/wp-content\/uploads\/2024\/02\/image-1-300x142.png 300w\" sizes=\"(max-width: 570px) 100vw, 570px\" \/><\/a><\/figure>\n\n\n\n<p><strong>Grantor:<\/strong> Croatian Science Foundation\u00a0<br><strong>Project duration:<\/strong> 2021. do 2025.\u00a0<br><strong>Total funding:<\/strong> <strong>\u202f<\/strong>679.000,00<strong> <\/strong>HRK\u00a0<\/p>\n\n\n\n<p><strong>Project team<\/strong>&nbsp;<\/p>\n\n\n\n<p>Principal investigator&nbsp;&nbsp;<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>prof. dr. sc. Gordana Blagojevi\u0107 Zagorac, dr. med.\u00a0<\/li>\n<\/ul>\n\n\n\n<p>Research team:&nbsp;<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>izv. prof. dr. sc. Tamara Guli\u0107 mag. biol.\u00a0\u00a0<\/li>\n\n\n\n<li>Valentino Pavi\u0161i\u0107\u202fdr. med.\u00a0\u00a0<\/li>\n\n\n\n<li>Silvija Lukanovi\u0107 Juri\u0107 dr.med.\u00a0<\/li>\n\n\n\n<li>Natalia Jug Vu\u010dko, mag. pharm. inv.\u00a0<\/li>\n<\/ul>\n\n\n\n<p><strong>Brief description<\/strong>\u00a0\u00a0<\/p>\n\n\n\n<p>Arf proteins are small GTPases that, through the recruitment of effector proteins, organize the cell cytoskeleton and change the dynamics of membranes, thus regulating transport within the secretory and endocytic systems, cell division and migration. Arf proteins are divided into three classes based on their sequence homology. Class I includes Arf1, Arf2 and Arf3, class II Arf4 and Arf5, while Arf6 is the only representative of class III. Just like other small GTPases, Arf proteins function as molecular switches because they cycle between their inactive (GDP-bound) and active (GTP-bound) forms. When inactivated, Arfs are mainly diffused throughout the cytoplasm, and are activated on cell membranes at sites where guanine nucleotide exchange factors (GEFs) are found. GEF proteins mediate the exchange of GDP for GTP, which causes conformational changes of Arf proteins and results in their tight binding to membranes and the recruitment of effector molecules located in close proximity. The endogenous GTPase activity of Arf proteins is extremely low and therefore GAP proteins are required for their inactivation, which, by stimulating the hydrolysis of GTP, lead to their inactivation. After hydrolysis of GTP, Arf1 and Arf3 are released from the membranes, while Arf4, Arf5, and Arf6 may in some cases still remain bound to the membrane.&nbsp;<\/p>\n\n\n\n<p>Cytomegaloviruses (CMV) are widespread DNA viruses from the herpesvirus family that, after acute, mostly asymptomatic infection, enter a latent phase from which they can be reactivated at any time and lead to life-threatening conditions in immunocompromised people. Already during the early phase of CMV infection, there is a massive reorganization of cellular functions, including the reorganization of membrane compartments and the cell cytoskeleton, which ultimately results in the formation of a cytoplasmic virion assembly compartment (cVACa). cVAC is a large, cylindrical, juxtanuclear-located compartment that has phenotypic characteristics of many intracellular compartments, including early endosomes, recycling endosomes, and the trans-Golgi network (TGN). Although the function of Arf proteins has been investigated in the pathogenesis of many bacterial and viral infections, and it is known that the activation of Arf1 and Arf6 proteins is an important factor in the virulence of <em>L. pneumophila<\/em>, <em>R. prowazekii and&nbsp;<\/em> <em>Salmonella bacteria&nbsp;<\/em> and single-stranded RNA viruses such as Hepatitis C virus, coronavirus and HIV, very little is known about the role of Arf protein in CMV infection. Unlike other pathogens that only use the cellular machinery to run their own life cycle, the characteristic of herpesviruses is extensive rearrangement of host cell organelles and in some cases even the formation of new compartments, which is the characteristic of CMV. Therefore, it is logical to expect that Arf proteins will be an important factor in the virulence of cytomegaloviruses, i.e. the entire herpesvirus family.&nbsp;<\/p>\n\n\n\n<p>This research would greatly contribute to the understanding of the role of Arf proteins in the replication cycle of CMV, that is, this research would determine whether Arf proteins are necessary for the entry of the virus into the cell, its replication and the formation of cVAC. Furthermore, through the analysis of the most important Arf GEF and Arf GAP proteins that interact with Arf proteins during CMV infection, and which are responsible for their activation\/inactivation, new knowledge about the specificity and localization of Arf-regulatory proteins would be analysed, which could also apply to uninfected cells. Furthermore, a major breakthrough for this research would be the determination of the gene region of the virus, responsible for the reorganization of the Arf system of host cells during CMV infection. Understanding how CMVs lead to reorganization of the endosomal system of the host cell, which results in evasion of immune response and viral replication, would create a platform for development of new antiviral drugs.&nbsp;<\/p>\n\n\n\n<p><strong>Publications<\/strong><\/p>\n\n\n\n<ol class=\"wp-block-list\">\n<li>Pavi\u0161i\u0107 V, Mahmutefendi\u0107 Lu\u010din H, Blagojevi\u0107 Zagorac G, Lu\u010din P. Arf GTPases Are Required for the Establishment of the Pre-Assembly Compartment in the Early Phase of Cytomegalovirus Infection. Life (Basel). 2021 Aug 23;11(8):867. doi: 10.3390\/life11080867. PMID: 34440611; PMCID: PMC8399710.<\/li>\n\n\n\n<li>Mahmutefendi\u0107 Lu\u010din H, Blagojevi\u0107 Zagorac G, Marceli\u0107 M, Lu\u010din P. Host Cell Signatures of the Envelopment Site within Beta-Herpes Virions.\u00a0<em>International Journal of Molecular Sciences<\/em>. 2022; 23(17):9994. https:\/\/doi.org\/10.3390\/ijms23179994<\/li>\n\n\n\n<li>Lu\u010din P, Mahmutefendi\u0107 Lu\u010din H, Blagojevi\u0107 Zagorac G. Cytomegaloviruses reorganize endomembrane system to intersect endosomal and amphisome-like egress pathway. Front Cell Dev Biol. 2023 Dec 19;11:1328751. doi: 10.3389\/fcell.2023.1328751. PMID: 38178873; PMCID: PMC10766366.<\/li>\n<\/ol>\n\n\n\n<p><strong>Proceedings Paper<\/strong><\/p>\n\n\n\n<ol class=\"wp-block-list\">\n<li>Valentino Pavi\u0161i\u0107, Natalia Jug Vu\u010dko, Hana Mahmutefendi\u0107 Lu\u010din, Ljerka Karleu\u0161a, Pero Lu\u010din, Gordana Blagojevi\u0107 Zagorac. Cytomegaloviruses induce massive reorganization of Arf proteins in theearly phase of infection. Abstracts of ECI 2021; 6th European Congress of Immunology. 1\u20104 September 2021. Virtual meeting. (European Journal of Immunology Volume 51, Suppl. 1, August 2021)<\/li>\n\n\n\n<li>Valentino Pavi\u0161i\u0107, Hana Mahmutefendi\u0107 Lu\u010din, Tamara Guli\u0107, Natalia Jug Vu\u010dko, Pero Lu\u010din1,2 and Gordana Blagojevi\u0107 Zagorac. MCMV induces activation and accumulation of Arf6 GTPase on membranes of virion assembly compartment. 2021 Annual Meeting of the Croatian Immunological Society, Trogir, 23.-25.09.2021.<\/li>\n\n\n\n<li>Valentino Pavi\u0161i\u0107, Hana Mahmutefendi\u0107 Lu\u010din, Natalia Jug Vu\u010dko, Pero Lu\u010din, Gordana Blagojevi\u0107 Zagorac. Arf proteins and their GEFs are generally excluded from outer part of murine cytomegalovirus assembly compartment in the late phase of MCMV infection15<sup>th<\/sup>Annual Meeting of Croatian Physiological Society with lnternational Participation, Zagreb 07-08.10.2021.<\/li>\n\n\n\n<li>Valentino Pavi\u0161i\u0107, Hana Mahmutefendi\u0107 Lu\u010din, Pero Lu\u010din, Gordana Blagojevi\u0107 Zagorac. Arf proteins accumulate in the citomegalovirus assembly compartment during the early phase of infection. The 45th FEBS Virtual Congress. 3-8 July 2021. Virtual meeting.<\/li>\n\n\n\n<li>Pavi\u0161i\u0107, Valentino; Mahmutefendi\u0107 Lu\u010din, Hana; Lu\u010din, Pero; Blagojevi\u0107 Zagorac, Gordana. Arf1 and Arf6 Are Required for the Establishment of Murine Cytomegalovirus Infection. 46<sup>th<\/sup>\u00a0International Herpesvirus Workshop. Virtual meeting, SAD, 25.7. \u2013 29.7. 2022.<\/li>\n\n\n\n<li>Pavi\u0161i\u0107, Valentino; Mahmutefendi\u0107 Lu\u010din, Hana; Lukanovi\u0107 Juri\u0107, Silvija; Lu\u010din, Pero; Blagojevi\u0107 Zagorac, Gordana. Arf1 and Arf6 GTPases are required for intracellular transport of cytomegalovirus virions. 3<sup>rd<\/sup>\u00a0Regional Congress of Physiological Societies and 5<sup>th<\/sup>\u00a0Congress of Croatian Physiological Society. Plitvice, Hrvatska, 22.09. \u2013 25.09. 2022.<\/li>\n\n\n\n<li><a href=\"https:\/\/www.unirepository.svkri.uniri.hr\/user\/profile\/mbz\/259873\">Blagojevi\u0107 Zagorac, Gordana<\/a>;\u00a0<a href=\"https:\/\/www.unirepository.svkri.uniri.hr\/user\/profile\/mbz\/334545\">Karleu\u0161a, Ljerka<\/a>; Viduka, Ivona;\u00a0<a href=\"https:\/\/www.unirepository.svkri.uniri.hr\/user\/profile\/mbz\/352613\">Jug Vu\u010dko, Natalia<\/a>;\u00a0<a href=\"https:\/\/www.unirepository.svkri.uniri.hr\/user\/profile\/mbz\/349364\">Pavi\u0161i\u0107, Valentino<\/a>;\u00a0<a href=\"https:\/\/www.unirepository.svkri.uniri.hr\/user\/profile\/mbz\/247686\">Mahmutefendi\u0107 Lu\u010din, Hana<\/a>;\u00a0<a href=\"https:\/\/www.unirepository.svkri.uniri.hr\/user\/profile\/mbz\/142314\">Lu\u010din, Pero<\/a>. BIG, GBF and BRAG ARF GEFS are required for the progression of immediate-early and early phase of MCMV infection. Congress of the Croatian Society of Biochemistry and Molecular Biology HDBMB22: From Science to Knowledge. Brela, Hrvatska, 28.09. \u2013 01.10. 2022.<\/li>\n\n\n\n<li>Blagojevi\u0107 Zagorac, Gordana; Guli\u0107, Tamara; Pavi\u0161i\u0107, Valentino; Mahmutefendi\u0107 Lu\u010din, Hana; Lukanovi\u0107 Juri\u0107, Silvija; Lu\u010din, Pero. Activation of Arf GTPases during murine cytomegalovirus infection. Annual meeting of the Croatian Immunological Society 2022. Sveti Martin na Muri, Hrvatska, 06.10. \u2013 08.10. 2022.<\/li>\n\n\n\n<li>\u0160timac, Igor; Blagojevi\u0107 Zagorac, Gordana; Marceli\u0107, Marina; Lu\u010din, Pero; Mahmutefendi\u0107 Lu\u010din, Hana. Rab10 GTPase is involved in membrane remodeling to form assembly compartment in the early phase of murine cytomegalovirus infection. 3<sup>rd<\/sup>\u00a0Regional Congress of Physiological Societies and 5<sup>th<\/sup>\u00a0Congress of Croatian Physiological Society. Plitvice, Hrvatska, 22.09. \u2013 25.09. 2022.<\/li>\n\n\n\n<li>Viduka, Ivona; \u0160timac, Igor; Guli\u0107, Tamara; Blagojevi\u0107 Zagorac, Gordana; Mahmutefendi\u0107 Lu\u010din, Hana; Lu\u010din, Pero. Suppression of Early Endosomal Sorting Nexins Affects Murine Cytomegalovirus Envelopment and Egress. 46<sup>th<\/sup>\u00a0International Herpesvirus Workshop. Virtual meeting, SAD, 25.7. \u2013 29.7. 2022.<\/li>\n\n\n\n<li>Marceli\u0107, Marina; Mahmutefendi\u0107 Lu\u010din, Hana; Jurak Begonja, Antonija; Blagojevi\u0107 Zagorac, Gordana; Viduka, Ivona; Lu\u010din, Pero. Endosomal Phosphatidylinositol-3-phosphate is Essential for the Final Assembly of CMV Virions. 46<sup>th\u00a0<\/sup>International Herpesvirus Workshop. Virtual meeting, SAD, 25.7. \u2013 29.7. 2022.<\/li>\n\n\n\n<li>\u0160timac, Igor; Radi\u0107, Barbara; Blagojevi\u0107 Zagorac, Gordana; Marceli\u0107, Marina; Lisni\u0107, Berislav; Lu\u010din, Pero; Mahmutefendi\u0107 Lu\u010din, Hana. EHBP1 and Rabin8 GTPase recruit Rab10 GTPase in Murine cytomegalovirus assembly compartment. The Annual Meeting of the Croatian Immunological Society. , Hrvatska, 05.10. \u2013 07.10. 2023.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"<p>Grantor: Croatian Science Foundation\u00a0Project duration: 2021. do 2025.\u00a0Total funding: \u202f679.000,00 HRK\u00a0 Project team&nbsp; Principal investigator&nbsp;&nbsp; Research team:&nbsp; Brief description\u00a0\u00a0 Arf proteins are small GTPases that, through the recruitment of effector proteins, organize the cell cytoskeleton and change the dynamics of membranes, thus regulating transport within the secretory and endocytic systems, cell division and migration. Arf [&hellip;]<\/p>\n","protected":false},"author":7,"featured_media":0,"parent":13412,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"ub_ctt_via":"","footnotes":""},"class_list":["post-26261","page","type-page","status-publish","hentry"],"acf":[],"featured_image_src":null,"_links":{"self":[{"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/pages\/26261","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/comments?post=26261"}],"version-history":[{"count":1,"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/pages\/26261\/revisions"}],"predecessor-version":[{"id":26262,"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/pages\/26261\/revisions\/26262"}],"up":[{"embeddable":true,"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/pages\/13412"}],"wp:attachment":[{"href":"https:\/\/medri.uniri.hr\/en\/wp-json\/wp\/v2\/media?parent=26261"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}