PuSH - Publikationsserver des Helmholtz Zentrums München

Hofmann, S.* ; Plank, V.* ; Groitl, P.* ; Skvorc, N.* ; Hofmann, K.* ; Luther, J.* ; Ko, C. ; Zimmerman, P.* ; Bruss, V. ; Stadler, D. ; Carpentier, A.* ; Rezk, S.* ; Nassal, M.* ; Protzer, U. ; Schreiner, S.

SUMO modification of hepatitis B virus core mediates nuclear entry, promyelocytic leukemia nuclear body association, and efficient formation of covalently closed circular DNA.

Microbiol. Spectr. 11:e0044623 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Persistence of hepatitis B virus (HBV) infection is due to a nuclear covalently closed circular DNA (cccDNA), generated from the virion-borne relaxed circular DNA (rcDNA) genome in a process likely involving numerous cell factors from the host DNA damage response (DDR). The HBV core protein mediates rcDNA transport to the nucleus and likely affects stability and transcriptional activity of cccDNA. Our study aimed at investigating the role of HBV core protein and its posttranslational modification (PTM) with SUMO (small ubiquitin-like modifiers) during the establishment of cccDNA. HBV core protein SUMO PTM was analyzed in His-SUMO-overexpressing cell lines. The impact of HBV core SUMOylation on association with cellular interaction partners and on the HBV life cycle was determined using SUMOylation-deficient mutants of the HBV core protein. Here, we show that the HBV core protein is posttranslationally modified by the addition of SUMO and that this modification impacts nuclear import of rcDNA. By using SUMOylation-deficient HBV core mutants, we show that SUMO modification is a prerequisite for the association with specific promyelocytic leukemia nuclear bodies (PML-NBs) and regulates the conversion of rcDNA to cccDNA. By in vitro SUMOylation of HBV core, we obtained evidence that SUMOylation triggers nucleocapsid disassembly, providing novel insights into the nuclear import process of rcDNA. HBV core protein SUMOylation and subsequent association with PML bodies in the nucleus constitute a key step in the conversion of HBV rcDNA to cccDNA and therefore a promising target for inhibiting formation of the HBV persistence reservoir. IMPORTANCE HBV cccDNA is formed from the incomplete rcDNA involving several host DDR proteins. The exact process and the site of cccDNA formation are poorly understood. Here, we show that HBV core protein SUMO modification is a novel PTM regulating the function of HBV core. A minor specific fraction of the HBV core protein resides with PML-NBs in the nuclear matrix. SUMO modification of HBV core protein mediates its recruitment to specific PML-NBs within the host cell. Within HBV nucleocapsids, SUMOylation of HBV core induces HBV capsid disassembly and is a prerequisite for nuclear entry of HBV core. SUMO HBV core protein association with PML-NBs is crucial for efficient conversion of rcDNA to cccDNA and for the establishment of the viral persistence reservoir. HBV core protein SUMO modification and the subsequent association with PML-NBs might constitute a potential novel target in the development of drugs targeting the cccDNA.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Hbv ; Hbv Core Protein ; Pml-nbs ; Sumo ; Chronic Infection; Protein Sumoylation; Pml; Bodies; Transcription; Replication; Binding; Sites; Pcna; Phosphorylation; Degradation
ISSN (print) / ISBN 2165-0497
e-ISSN 2165-0497
Zeitschrift Microbiology Spectrum
Quellenangaben Band: 11, Heft: 3, Seiten: , Artikelnummer: e0044623 Supplement: ,
Verlag American Society for Microbiology (ASM)
Verlagsort 1752 N St Nw, Washington, Dc 20036-2904 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen Manchot Stiftung e.V.
Drager Stiftung e.V.
Deutsche Krebshilfe e.V.
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy
German Research Foundation)
Deutsche Forschungsgemeinschaft (DFG