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35Hepatitis B virus (HBV) continues to pose a serious public health risk and is one 36 of the major causes of chronic liver disease and hepatocellular carcinoma. Current 37 antiviral therapy does not effectively eradicate HBV and, thus, further investigation 38 into the mechanisms employed by HBV to allow for invasion of host cells, is critical 39 for the development of novel therapeutic agents. Sodium-taurocholate cotransporting 40 polypeptide (NTCP) has been identified as a functional receptor for HBV. However, 41 the specific mechanism by which HBV and NTCP interact remains unclear. Herein 42 we show that the expression of E-cadherin was upregulated in cells expressing HBV, 43 while knockdown of E-cadherin in HepG2-NTCP cells, HepaRG cells and primary 44 human hepatocytes served to significantly inhibit infection by HBV and HBV 45 pseudotyped particles. Alternatively, exogenous E-cadherin expression was found to 46 significantly enhance HBV uptake by HepaRG cells. Further, mechanistic studies 47 identified glycosylated NTCP localized to the cell membrane via E-cadherin binding, 48 which subsequently allowed for more efficient binding between NTCP and the preS1 49 of the large HBV surface proteins. E-cadherin was also found to play a key role in 50 establishing and maintaining hepatocyte polarity, which is essential for efficient HBV 51 infection. These observations suggest that E-cadherin facilitates HBV entry through 52 regulation of NTCP distribution and hepatocyte polarity. 53 54 Author Summary 55 Hepatitis B Virus (HBV) still seriously endangers public health. It is very 3 56important to understand the mechanism of HBV invading host cells for developing 57 new therapy target. Sodium-taurocholate cotransporting polypeptide (NTCP) is the 58 key receptor mediating HBV invasion, while other molecules also exhibit important 59 roles in ensuring efficient and productive HBV infection. This study reports that 60 E-cadherin facilitates HBV entry by directly interacting with glycosylated NTCP to 61 mediate its distribution on the hepatocyte membrane and also affects the efficacy of 62 HBV invasion by influncing hepatocyte polarity. 63 64 Introduction 65 Hepatitis B virus (HBV), a member of the Hepadnaviridae family, is a small, 66 enveloped DNA virus [1] that infects human liver parenchymal cells. Although the 67 widespread use of vaccines has greatly reduced the rate of infection, HBV continues 68 to pose a serious threat to global health, affecting more than 350 million individuals 69 worldwide, all of whom are at increased risk of developing liver cirrhosis and 70 hepatocellular carcinoma (HCC) [2]. Current therapeutic regimens that employ 71 direct-acting antivirals, with or without ribavirin, have significantly increased the 72 prevalence of escape mutants and cause serious adverse effects, thus, eliciting a low 73 curative rate in HBV patients [3].74 Furthermore, the lack of effective therapeutic options for HBV is partially due to 75 our incomplete understanding of the HBV life cycle, including the sta...