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ATM-Dependent Phosphorylation of Hepatitis B Core Protein in Response to Genotoxic Stress
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SYSNO ASEP 0550723 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název ATM-Dependent Phosphorylation of Hepatitis B Core Protein in Response to Genotoxic Stress Tvůrce(i) Lubyová, Barbora (UOCHB-X) ORCID
Tikalová, Eva (UOCHB-X)
Krulová, Kristýna (UOCHB-X)
Hodek, Jan (UOCHB-X) RID, ORCID
Zábranský, Aleš (UOCHB-X) RID, ORCID
Hirsch, Ivan (UOCHB-X) ORCID, RID
Weber, Jan (UOCHB-X) RID, ORCIDČíslo článku 2438 Zdroj.dok. Viruses. - : MDPI
Roč. 13, č. 12 (2021)Poč.str. 24 s. Jazyk dok. eng - angličtina Země vyd. CH - Švýcarsko Klíč. slova HBV core protein ; serine phosphorylation ; DNA damage response pathway ; ATM ; ATR Obor OECD Virology CEP EF16_019/0000729 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LTC20065 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000737379100001 EID SCOPUS 85121461539 DOI 10.3390/v13122438 Anotace Chronic hepatitis caused by infection with the Hepatitis B virus is a life-threatening condition. In fact, 1 million people die annually due to liver cirrhosis or hepatocellular carcinoma. Recently, several studies demonstrated a molecular connection between the host DNA damage response (DDR) pathway and HBV replication and reactivation. Here, we investigated the role of Ataxia-telangiectasia-mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) PI3-kinases in phosphorylation of the HBV core protein (HBc). We determined that treatment of HBc-expressing hepatocytes with genotoxic agents, e.g., etoposide or hydrogen peroxide, activated the host ATM-Chk2 pathway, as determined by increased phosphorylation of ATM at Ser1981 and Chk2 at Thr68. The activation of ATM led, in turn, to increased phosphorylation of cytoplasmic HBc at serine-glutamine (SQ) motifs located in its C-terminal domain. Conversely, down-regulation of ATM using ATM-specific siRNAs or inhibitor effectively reduced etoposide-induced HBc phosphorylation. Detailed mutation analysis of S-to-A HBc mutants revealed that S170 (S168 in a 183-aa HBc variant) is the primary site targeted by ATM-regulated phosphorylation. Interestingly, mutation of two major phosphorylation sites involving serines at positions 157 and 164 (S155 and S162 in a 183-aa HBc variant) resulted in decreased etoposide-induced phosphorylation, suggesting that the priming phosphorylation at these serine-proline (SP) sites is vital for efficient phosphorylation of SQ motifs. Notably, the mutation of S172 (S170 in a 183-aa HBc variant) had the opposite effect and resulted in massively up-regulated phosphorylation of HBc, particularly at S170. Etoposide treatment of HBV infected HepG2-NTCP cells led to increased levels of secreted HBe antigen and intracellular HBc protein. Together, our studies identified HBc as a substrate for ATM-mediated phosphorylation and mapped the phosphorylation sites. The increased expression of HBc and HBe antigens in response to genotoxic stress supports the idea that the ATM pathway may provide growth advantage to the replicating virus. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2022 Elektronická adresa https://doi.org/10.3390/v13122438
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