Endoplasmic Reticulum Aminopeptidase 1 Is Involved in Anti-viral Immune Response of Hepatitis B Virus by Trimming Hepatitis B Core Antigen to Generate 9-Mers Peptides

• Published in: Frontiers in microbiology Vol. 13; p. 829241
• Main Authors: Liu, Huanhuan, Hu, Bingqi, Huang, Junfeng, Wang, Qin, Wang, Feier, Pan, Faming, Chen, Liwen
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04.05.2022
• Subjects: antigen presentation; endoplasmic reticulum aminopeptidase 1; hepatitis B; immune response; major histocompatibility complex class I; Microbiology; endoplasmic reticulum aminopeptidase 1; antigen presentation; hepatitis B; immune response; major histocompatibility complex class I
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2022.829241

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a processing enzyme of antigenic peptides presented to major histocompatibility complex (MHC) class I molecules. ERAP1-dependent trimming of epitope repertoire determines an efficacy of adoptive CD8 + T-cell responses in several viral diseases; however, its role in hepatitis B virus (HBV) infection remains unknown. Here, we show that the serum level of ERAP1 in patients with chronic hepatitis B (CHB) ( n = 128) was significantly higher than that of healthy controls ( n = 44) (8.78 ± 1.82 vs. 3.52 ± 1.61, p < 0.001). Furthermore, peripheral ERAP1 level is moderately correlated with HBV DNA level in patients with CHB ( r = 0.731, p < 0.001). HBV-transfected HepG2.2.15 cells had substantially increased ERAP1 expression and secretion than the germline HepG2 cells ( p < 0.001). The co-culture of ERAP1-specific inhibitor ERAP1-IN-1 pretreated HepG2.2.15 cells or ERAP1 knockdown HepG2.2.15 cells with CD8 + T cells led to 14–24% inhibition of the proliferation of CD8 + T cells. Finally, liquid chromatography tandem mass spectrometry (LC-MS/MS) test demonstrated that ERAP1-IN-1 blocks completely the production of a 9-mers peptide (30–38, LLDTASALY) derived from Hepatitis B core antigen (HBcAg). The predictive analysis by NetMHCpan-4.1 server showed that human leukocyte antigen (HLA)-C*04:01 is a strong binder for the 9-mers peptide in HepG2.2.15 cells. Taken together, our results demonstrated that ERAP1 trims HBcAg to produce 9-mers LLDTASALY peptides for binding onto HLA-C*04:01 in HepG2.2.15 cells, facilitating the potential activation of CD8 + T cells.