The Prange laboratory studies host/pathogen interactions with special focus on human hepatitis B and hepatitis D viruses. The program of basic and translational research aimed at developing a better understanding of these pathogens that can be used to generate more effective treatment strategies. Human hepatitis B virus (HBV) is a global pathogen responsible for acute and chronic liver disease. Worldwide an estimated 250 million individuals are chronically infected and potentially develop liver cirrhosis and hepatocellular carcinoma. Persistent HBV infections are currently incurable. With the aim to improve knowledge of the biology of HBV infection and to seek for more effective antiviral strategies, we are studying HBV particle morphogenesis and its coordination by host cell factors. As the prototype member of the hepadnavirus family, HBV is an enveloped, DNA-containing pararetrovirus that replicates by reverse transcription. HBV produces not only complete infectious virions, but also non-enveloped capsids and empty envelope particles that are thought to support viral transmission and viral immune evasion. In order to form and release its particle types, HBV exploits different strategies and host factors. (1) Virions bud at intracellular membranes by the exploitation of cellular Rab GTPases, ubiquitin adaptors, ubiquitin ligases and specific proteins of the multivesicular endosome system, termed ESCRTs. (2) Naked (nucleo)capsids are formed with the assistance of Rab33B and its autophagosomal Atg5/12/16L1 effector protein and are released in an uncommon, non-lytic process using the cellular Alix protein. (3) Empty envelope particles mature in the secretory system and require the assistance of chaperones and probably Rab-guided transport pathways. The participating cellular protein networks and mechanisms and their differential use by the virus are not fully resolved in their complexity, hierarchy and regulation and will be characterized in continuing works using a range of cell biology, virology, biochemical, and imaging approaches. Future research activities will also focus on the hepatitis D virus (HDV), a viroid that requires the HBV envelope for virion production and infectivity.
Bartusch, Christina, Prange Reinhild. EXCRT requirements for Murine Leukemia Virus Release. Viruses-Basel. 2016; 8 (4).
Doering Tatjana, Prange Reinhild. Rab33B and its autophagic Atg5/12/16L1 effector assist in hepatitis B virus naked capsid formation and release. CELLULAR MICROBIOLOGY. 2015; 17 (5): 747-764.
Stieler Jens T., Prange Reinhild Involvement of ESCRT-II in Hepatitis B Virus Morphogenesis. PLOS ONE. 2014; 9(3).
Mades A, Gotthardt K, Awe K, Stieler J, Doering T, Fueser S, Prange R. (2012). Role of Human Sec63 in Modulating the Steady-State Levels of Multi-Spanning Membrane Proteins. PLOS ONE. 7 (11).
Prange R. Host factors involved in hepatitis B virus maturation, assembly, and egress. Med Microbiol Immunol. 2012;201(4):449-61.
Bardens A, Doring T, Stieler J, Prange R. (2011). Alix regulates egress of hepatitis B virus naked capsid particles in an ESCRT-independent manner. Cell. Microbiol. 13(4):602-619.
Doring T, Gotthardt K, Stieler J, Prange R. (2010). gamma 2-Adaptin is functioning in the late endosomal sorting pathway and interacts with ESCRT-I and -III subunits. BBA-Molecular Cell Research. 1803(11):1252-1264.
M. Rost, T. Döring, and R. Prange (2008). g2-Adaptin, a ubiquitin-interacting adaptor, is a substrate to coupled ubiquitination by the ubiquitin ligase Nedd4 and functions in the endosomal pathway. J. Biol. Chem. 283: 32119-32130.
A. Funk, M. Mhamdi, H. Hohenberg, J. Heeren, R. Reimer, C. Lambert, R. Prange, H. Sirma (2008). Duck hepatitis B virus requires cholesterol for endosomal escape during virus entry. J. Virol. 82: 10532-10542.
Awe K, Lambert C, Prange R. (2008). Mammalian BiP controls posttranslational ER translocation of the hepatitis B virus large envelope protein. FEBS Lett. 582: 3179-3184.
C. Lambert, T. Döring and R. Prange (2007). Hepatitis B virus maturation is sensitive to functional Inhibition of ESCRT-III, Vps4, and g2-Adaptin. J. Virol. 81: 9050-9060.
C. Lambert and R. Prange (2007). Posttranslational N-glycosylation of the hepatitis B virus large envelope protein. Virol. J. 4: 45-53.
M. Rost, S. Mann, C. Lambert, T. Döring, N. Thomé and R. Prange (2006). g2-Adaptin, a novel ubiquitin-interacting adaptor, and Nedd4 ubiquitin ligase control hepatitis B virus maturation. J. Biol. Chem. 281: 29297-29308.
C. Lambert and R. Prange (2004). Development and characterization of a 293 cell line with regulatable expression of the hepatitis B virus large envelope protein. J. Virol. Methods 121:181-190.
C. Lambert, N. Thomé, C. J. Kluck and R Prange. (2004). Functional incorporation of green fluorescent protein into hepatitis B virus envelope particles. Virology 330: 158-167.
C. Lambert, S. Mann and R. Prange (2004). Assessment of determinants affecting the dual topology of hepadnaviral large envelope proteins. J. Gen. Virol. 85: 1221-1225.
P. Gerner, H. Schäfer, R. Prange, D. Pravitt and S. Wirth (2003). Functional analysis of a rare HBV deletion mutant in chronically infected children. Pediatric Research 53: 891-897.
C. Lambert and R. Prange (2003). Chaperone action in the posttranslational topological reorientation of the hepatitis B virus large envelope protein: implications for translocational regulation. Proc. Natl. Acad Sci. USA 100: 5199-5204.