Apolipoprotein H drives hepatitis B surface antigen retention and endoplasmic reticulum stress during hepatitis B virus infection.

Yaming Liu, Jessica L Maiers, Yajuan Rui, Xiaoming Jiang, Bayasi Guleng, Jianlin Ren

The international journal of biochemistry & cell biology 2021 Feb

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Apolipoprotein H (APOH), also known as beta2-glycoprotein I (beta2-GPI), is an acute phase protein in hepatitis B virus (HBV) infection and binds to hepatitis B surface antigen (HBsAg) with high-affinity. APOH expression is upregulated by HBV and the large surface protein (LHBs), but also elevated in HBV-related hepatoma cells. Previous studies show that intracellular retention of HBsAg induces endoplasmic reticulum (ER) stress, a key driver of hepatocyte damage during chronic liver injury, but the mechanisms are unclear. We hypothesize that APOH mediates HBV-induced ER stress through increased retention of HBsAg. VR-APOH-myc and VR-LHBs-flag plasmids were constructed by PCR using pcDNA3.1(-)-APOH or an HBV expression vector, respectively. APOH and ER stress markers were examined at protein and mRNA levels by Western Blot or RT-qPCR. HBsAg titer was assayed by ELISA. RNA-seq was performed to elucidate the transcriptional impact of APOH manipulation in HBV-producing cells (HepG2.2.15 cells). We found that HBV upregulates APOH expression in 293 T cells, and APOH overexpression subsequently inhibits secretion of HBsAg. Next, we show that LHBs overexpression in conjunction with APOH leads to ER stress in 293 T cells, as evidenced by production of the binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), as well as increased splicing of X-box binding protein 1 (XBP1). We further observed that loss of beta2-GPI reduced CHOP expression in HepG2.2.15 cells, while beta2-GPI overexpression enhanced CHOP production. The interaction of beta2-GPI and HBV initiates ER stress through driving intracellular retention of HBsAg and activates the UPR. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Yaming Liu, Jessica L Maiers, Yajuan Rui, Xiaoming Jiang, Bayasi Guleng, Jianlin Ren. Apolipoprotein H drives hepatitis B surface antigen retention and endoplasmic reticulum stress during hepatitis B virus infection. The international journal of biochemistry & cell biology. 2021 Feb;131:105906