Abstract
Hepatitis B virus (HBV) infection remains a major global health problem and the primary cause of cirrhosis and hepatocellular carcinoma (HCC). HBV intrusion into host cells is prompted by virus–receptor interactions in clathrin-mediated endocytosis. Here, we report a comprehensive view of the cellular endocytosis-associated transcriptome, proteome and ubiquitylome upon HBV infection. In this study, we quantified 273 genes in the transcriptome and 190 endocytosis-associated proteins in the proteome by performing multi-omics analysis. We further identified 221 Lys sites in 77 endocytosis-associated ubiquitinated proteins. A weak negative correlation was observed among endocytosis-associated transcriptome, proteome and ubiquitylome. We found 33 common differentially expressed genes (DEGs), differentially expressed proteins (DEPs), and Kub-sites. Notably, we reported the HBV-induced ubiquitination change of secretory carrier membrane protein (SCAMP1) for the first time, differentially expressed across all three omics data sets. Overexpression of SCAMP1 efficiently inhibited HBV RNAs/pgRNA and secreted viral proteins, whereas knockdown of SCAMP1 significantly increased viral production. Mechanistically, the EnhI/XP, SP1, and SP2 promoters were inhibited by SCAMP1, which accounts for HBV X and S mRNA inhibition. Overall, our study unveils the previously unknown role of SCAMP1 in viral replication and HBV pathogenesis and provides cumulative and novel information for a better understanding of endocytosis in response to HBV infection.
Highlights
Hepatitis B virus (HBV) is a major threat to human health, and it is estimated that there are 350–500 million people affected with chronic HBV infection worldwide. [1,2]
We found that HBV induced significant alterations in the host global ubiquitylome and proteome [17]
We found 170 differentially expressed genes (DEGs) (p ≤ 0.05) out of 273 quantified genes, 100 DEGs were up-regulated while 70 were down-regulated, 36 genes were changed more than two folds (19 up-regulated and 17 down-regulated) (Figure 1A and Supplementary Table S2)
Summary
Hepatitis B virus (HBV) is a major threat to human health, and it is estimated that there are 350–500 million people affected with chronic HBV infection worldwide. [1,2]. HBV internalization into cells is triggered by virus–receptor interactions in clathrin-mediated endocytosis (CME). It has been shown that the endocytosis-associated protein epidermal growth factor receptor (EGFR) mediates the internalization of sodium taurocholate co-transporting polypeptide (NTCP)-bound HBV via its endocytosis/sorting pathway [7]. Many aspects and the significance of how infection alters the host endocytosis process remained completely obscure [8,9]. We performed RNA sequencing, quantitative mass spectrometry, and Ubiscan analysis in HepG2.2.15 and HepG2 cell lines in three distinct biological replicates that were proceeded independently to explore HBV-mediated alterations in endocytosis associated proteins. We discovered the previously unknown antiviral function of endocytosis-associated protein SCAMP1 against HBV replication. Our findings provide valuable information to develop novel therapeutics and a comprehensive understanding of alterations of endocytosis-associated proteins in response to HBV infection
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