Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells

Herpes simplex virus 1 (HSV-1) on vaipallinen DNA virus, joka aiheuttaa rakkuloita sekä suun- että sukupuolielinten alueella. Lyyttinen infektio muokkaa tumalaminan rakennetta sekä aiheuttaa kromatiinin pakkautumisen tuman laitamille. Tumalaminan hajottaminen helpottaa kapsidien ulospääsyä tumasta,...

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Main Author: Hirvonen, Johanna
Other Authors: Matemaattis-luonnontieteellinen tiedekunta, Faculty of Sciences, Bio- ja ympäristötieteiden laitos, Department of Biological and Environmental Science, Jyväskylän yliopisto, University of Jyväskylä
Format: Master's thesis
Language:eng
Published: 2020
Subjects:
Online Access: https://jyx.jyu.fi/handle/123456789/70941
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author Hirvonen, Johanna
author2 Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Bio- ja ympäristötieteiden laitos Department of Biological and Environmental Science Jyväskylän yliopisto University of Jyväskylä
author_facet Hirvonen, Johanna Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Bio- ja ympäristötieteiden laitos Department of Biological and Environmental Science Jyväskylän yliopisto University of Jyväskylä Hirvonen, Johanna Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Bio- ja ympäristötieteiden laitos Department of Biological and Environmental Science Jyväskylän yliopisto University of Jyväskylä
author_sort Hirvonen, Johanna
datasource_str_mv jyx
description Herpes simplex virus 1 (HSV-1) on vaipallinen DNA virus, joka aiheuttaa rakkuloita sekä suun- että sukupuolielinten alueella. Lyyttinen infektio muokkaa tumalaminan rakennetta sekä aiheuttaa kromatiinin pakkautumisen tuman laitamille. Tumalaminan hajottaminen helpottaa kapsidien ulospääsyä tumasta, sillä nämä rakenteet tiettävästi estävät kapsidien liikettä. Lamiinien fosforylointia varten HSV-1 värvää avukseen solun kinaaseja sekä viruskinaasi Us3:n. Tässä tutkielmassa tutkimme lamiini A/C (LMNA) geenin C-terminaalin deleetion vaikutusta tumalaminaan sekä kromatiinin uudelleenjärjestäytymiseen HSV-1 infektiossa hiiren alkion fibroblasteissa. Kolmiulotteinen konfokaalimikroskopia paljasti kromatiinijakauman muuttuvan merkittävästi LMNA mutatoiduissa soluissa aiheuttaen voimakasta kromatiinin tiivistymistä tuman laitamille infektion edetessä, mikä myös vahvistettiin kvantitatiivisella analyysillä. Tämä osoittaa A- tyypin lamiinien vaikuttavan merkittävästi kromatiinin järjestäytymiseen tumassa. Viruksen Us3-kinaasin deleetion huomattiin aiheuttavan laajempaa kromatiinin tiivistymistä soluissa, joissa LMNA oli C-terminaalisesti deletoitu. Tämä viittaa siihen, että Us3:lla on keskeinen rooli viruksen aiheuttamassa isännän lamiini A/C:n fosforylaatiossa sekä myös kromatiinin uudelleenjärjestäytymisessä. Mielenkiintoisesti, western blot analyysimme paljasti lamiini B1:n ekspression merkittävän kasvun LMNA mutatoiduissa soluissa, mikä viittaa siihen, että lamiini B saattaa kompensoida LMNAn funktiota soluissa. Kaiken kaikkiaan lamiini A/C:lla näyttää oleva merkittävä rooli sekä tumalaminan että kromatiinin järjestäytymisessä HSV-1 infektion aikana. Herpes simplex virus type 1 (HSV-1) is an enveloped DNA virus causing lesions in the epithelium of oral and genital areas in humans. Lytic HSV-1 infection causes chromatin marginalisation to the nuclear periphery and disassembly of the nuclear lamina. Destruction of the lamina facilitates capsid egress since the lamina functions as a barrier between the capsids and their egress site at the nuclear envelope. The virus recruits cellular kinases as well as a viral kinase, Us3, to phosphorylate lamins, which leads to modification of the nuclear lamina. In this thesis, we investigated the effect of C-terminal deletion of the lamin A/C (LMNA) gene on the organisation of the nuclear lamina and chromatin during HSV-1 infection in mouse embryonic fibroblasts. Three-dimensional confocal microscopy analyses revealed that chromatin distribution was significantly altered in the LMNA mutated cells creating more extensive chromatin condensation to the nuclear rim, which was further confirmed with a quantitative analysis. This indicates that A-type lamins are essential for the spatial organisation of chromatin in infected cells. When the cells were infected with Us3 kinase deficient virus, we detected an increase in chromatin condensation in cells with the LMNA C-terminal deletion. This suggests that viral Us3 kinase plays an important role in the phosphorylation of host lamin A/C and the structural organisation of chromatin. Notably, the western blot analysis revealed that the deletion of LMNA C-terminus was accompanied by a significant increase in lamin B1 expression, suggesting that the loss of LMNA functionality was compensated in the cells. Altogether, lamin A/C seems to have a major role in both nuclear lamina and chromatin organisation during HSV-1 infection.
first_indexed 2020-06-26T20:00:33Z
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Lyyttinen infektio muokkaa tumalaminan rakennetta sek\u00e4 aiheuttaa kromatiinin pakkautumisen tuman laitamille. Tumalaminan hajottaminen helpottaa kapsidien ulosp\u00e4\u00e4sy\u00e4 tumasta, sill\u00e4 n\u00e4m\u00e4 rakenteet tiett\u00e4v\u00e4sti est\u00e4v\u00e4t kapsidien liikett\u00e4. Lamiinien fosforylointia varten HSV-1 v\u00e4rv\u00e4\u00e4 avukseen solun kinaaseja sek\u00e4 viruskinaasi Us3:n. T\u00e4ss\u00e4 tutkielmassa tutkimme lamiini A/C (LMNA) geenin C-terminaalin deleetion vaikutusta tumalaminaan sek\u00e4 kromatiinin uudelleenj\u00e4rjest\u00e4ytymiseen HSV-1 infektiossa hiiren alkion fibroblasteissa. Kolmiulotteinen konfokaalimikroskopia paljasti kromatiinijakauman muuttuvan merkitt\u00e4v\u00e4sti LMNA mutatoiduissa soluissa aiheuttaen voimakasta kromatiinin tiivistymist\u00e4 tuman laitamille infektion edetess\u00e4, mik\u00e4 my\u00f6s vahvistettiin kvantitatiivisella analyysill\u00e4. T\u00e4m\u00e4 osoittaa A- tyypin lamiinien vaikuttavan merkitt\u00e4v\u00e4sti kromatiinin j\u00e4rjest\u00e4ytymiseen tumassa. Viruksen Us3-kinaasin deleetion huomattiin aiheuttavan laajempaa kromatiinin tiivistymist\u00e4 soluissa, joissa LMNA oli C-terminaalisesti deletoitu. T\u00e4m\u00e4 viittaa siihen, ett\u00e4 Us3:lla on keskeinen rooli viruksen aiheuttamassa is\u00e4nn\u00e4n lamiini A/C:n fosforylaatiossa sek\u00e4 my\u00f6s kromatiinin uudelleenj\u00e4rjest\u00e4ytymisess\u00e4. Mielenkiintoisesti, western blot analyysimme paljasti lamiini B1:n ekspression merkitt\u00e4v\u00e4n kasvun LMNA mutatoiduissa soluissa, mik\u00e4 viittaa siihen, ett\u00e4 lamiini B saattaa kompensoida LMNAn funktiota soluissa. 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spellingShingle Hirvonen, Johanna Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells nuclear lamina Us3 Solu- ja molekyylibiologia Cell and molecular biology 4013 herpesvirukset herpesviruses
title Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells
title_full Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells
title_fullStr Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells
title_full_unstemmed Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells
title_short Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells
title_sort modification of lamin a c affects chromatin distribution in hsv 1 infected cells
title_txtP Modification of Lamin A/C affects chromatin distribution in HSV-1 infected cells
topic nuclear lamina Us3 Solu- ja molekyylibiologia Cell and molecular biology 4013 herpesvirukset herpesviruses
topic_facet 4013 Cell and molecular biology Solu- ja molekyylibiologia Us3 herpesvirukset herpesviruses nuclear lamina
url https://jyx.jyu.fi/handle/123456789/70941 http://www.urn.fi/URN:NBN:fi:jyu-202006265128
work_keys_str_mv AT hirvonenjohanna modificationoflaminacaffectschromatindistributioninhsv1infectedcells