Hepatitis E virus ORF1 encoded macro domain protein interacts with light chain subunit of human ferritin and inhibits its secretion

Abstract

Hepatitis E Virus (HEV) is the major causative agent of acute hepatitis in developing countries. Its genome has three open reading frames (ORFs)-called as ORF1, ORF2, and ORF3. ORF1 encodes nonstructural polyprotein having multiple domains, namely: Methyltransferase, Y domain, Protease, Macro domain, Helicase, and RNA-dependent RNA polymerase. In the present study, we show that HEV-macro domain specifically interacts with light chain subunit of human ferritin (FTL). In cultured hepatoma cells, HEV-macro domain reduces secretion of ferritin without causing any change in the expression levels of FTL. This inhibitory effect was further enhanced upon Brefeldin-A treatment. The levels of transferrin Receptor 1 or ferroportin, two important proteins in iron metabolism, remained unchanged in HEV-macro domain expressing cells. Similarly, there were no alterations in the levels of cellular labile iron pool and reactive oxygen species, indicating that HEV-macro domain does not influence cellular iron homeostasis/metabolism. As ferritin is an acute-phase protein, secreted in higher level in infected persons and HEV-macro domain has the property of reducing synthesis of inflammatory cytokines, we propose that by directly binding to FTL, macro domain prevents ferritin from entering into circulation and helps in further attenuation of the host immune response.

Immune system‑associated genes increase malignant progression and can be used to predict clinical outcome in patients with hepatocellular carcinoma

“…Ferritin light chain (FTL) is the light subunit of the ferritin protein, which is involved in iron release and uptake in tissues. Several allergic diseases, inflammation status and oxidative damage are associated with the roles of FTL, including systemic lupus erythematosus, cataracts, hepatitis E virus infection and Alzheimer's disease (42)(43)(44)(45)(46)(47). FTL also serves a role in cancer, where the dysfunction of iron metabolism is a hallmark of various types of cancer, and is involved drug resistance and malignant progression (48)(49)(50).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…It is believed that viral macrodomains can remove the MARylation and PARylation modification (167). The Hepeviridae, Togaviridae, and Coronaviridae families of viruses express conserved macrodomain proteins (531)(532)(533)(534)(535)(536)(537)(538)(539). Many of these macrodomains exhibit ADP-ribosylhydrolase activity (171,538,540,541).…”

Hepatitis E virus infection during pregnancy

“…ORF1-encoded macrodomain can inhibit the phosphorylation/activation of interferon regulatory factor 3 (IRF-3), thus possibly combating the host antiviral response [126]. In addition, the macrodomain can interact with the light chain subunit of human ferritin and inhibit its secretion, suggesting its possible role in suppressing the innate immune response [127]. These reports suggest the possible involvement of ORF1-encoded proteins in determining the outcome of HEV infections.…”