Abstract
Hepatitis B virus (HBV) infection is a global health problem that causes a wide range of pathological outcomes, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic inflammation via enhanced inflammation, oxidative stress-mediated DNA damage, and hepatocyte proliferation. In the natural course of HBV infection, the accumulation of naturally occurring mutations in the HBV genome can generate several mutant types of HBV-encoded proteins, including three different proteins in the S ORF (SHBs, MHBs, and LHBs) and HBcAg in the C ORF, which could contribute to enhanced ER stress in infected hepatocytes mainly via increased ER accumulation of mutant proteins. However, it seems that there may be distinct capacity and pathway in ER stress-induction and distinct resulting clinical outcomes between HBV variants. In addition, the role of HBxAg mutations in ER stress remains unknown. However, it has been reported that HBxAg itself could exert ER stress in infected cells, resulting in HCC generation in chronic HBV patients. To date, review papers regarding ER stress-mediated HBV mutation have been limited into a specific mutation type: preS2 deletion. So, in this review, we will discuss details about various mutation types in all four regions of the HBV genome (preS1, preS2, S, and C) related to ER stress and their distinct ER stress mechanisms and clinical outcomes in terms of mutation types.
Highlights
Hepatitis B virus (HBV) infection is responsible for the chronic infection of more than 240 million people worldwide [1,2]
Similar to PRKR-like endoplasmic reticulum kinase (PERK) and IRE1a, activating transcription factor 6 (ATF6) is covered by GRP78, but in the presence of Endoplasmic reticulum (ER) stress, ATF6 is released and translocated to the Golgi apparatus
Pollicino et al (2012) [16] screened 40 untreated CHB patients, and among them, 14 patients (35%) showed single or multiple preS or S mutations. They found a negative correlation between preS/S mutations and secreted HBV surface antigen levels (p = 0.005), that envelope proteins were restricted to the ER and that extracellular virion levels in mutants were lower than those in the WT
Summary
Hepatitis B virus (HBV) infection is responsible for the chronic infection of more than 240 million people worldwide [1,2]. HBV is a member of the Hepadnaviridae family and is a small enveloped DNA virus with a virion diameter of 42 nm containing four overlapping open reading frames (ORFs) named C, S, P, and X. These encode core proteins that form viral capsids; small (SHBs), medium (MHBs), and large (LHBs) envelope proteins that form subviral particles; a polymerase; and the HBx protein, respectively [4]. Sboe,einnrtehvisierweveide.wS,ow, ienwthililsdriesvciuesws ,dweteaiwlsilalbdoiusctumsus tdaetitoanilstyapbeosuitnmaulltfaotuiornretygpioenssinofatlhl efoHuBr Vreggeionnosmoef (tphreeSH1B, VpregSe2n,oSm, aen(dprCe)Sa1s, sporceiSat2e,dS,wainthdECR)satrsessosciaanteddthweiitrhdEisRtinscttreEsRs satnrdessth-ienidr udciisntignmct eEcRhasntirsemsssainndduccliinngicaml eocuhtacnomismess(aFnigducrlein1i)c.al outcomes (Figure 1)
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