Sec24C-Dependent Transport of Claudin-1 Regulates Hepatitis C Virus Entry

Abstract

Claudin-1 is a hepatitis C virus (HCV) coreceptor required for viral entry. Although extensive studies have focused on claudin-1 as an anti-HCV target, little is known about how the level of claudin-1 at the cell surface is regulated by host vesicular transport. Here, we identified an interaction between claudin-1 and Sec24C, a cargo-sorting component of the coat protein complex II (COPII) vesicular transport system. By interacting with Sec24C through its C-terminal YV, claudin-1 is transported from the endoplasmic reticulum (ER) and is eventually targeted to the cell surface. Blocking COPII transport inhibits HCV entry by reducing the level of claudin-1 at the cell surface. These findings provide mechanistic insight into the role of COPII vesicular transport in HCV entry. Tight junction protein claudin-1 is one of the cellular receptors for hepatitis C virus, which infects 185 million people globally. Its cellular distribution plays important role in HCV entry; however, it is unclear how the localization of claudin-1 to the cell surface is controlled by host transport pathways. In this paper, we not only identified Sec24C as a key host factor for HCV entry but also uncovered a novel mechanism by which the COPII machinery transports claudin-1 to the cell surface. This mechanism might be extended to other claudins that contain a C-terminal YV or V motif.

COPII cargo claudin‐12 promotes hepatitis C virus entry

“…To study the interaction between Sec24C and CLDN tails, we fused GST to a series of CLDN tails and performed GST pull‐down experiments and detected the samples with Sec24C antibody (Cell Signaling Technology, Inc. Boston, USA, catalog No.14676). Consistent with previous study, Sec24C associated with the tails from CLDN1, CLDN4, CLDN5, CLDN11, CLDN16 and CLDN19, all of which contained V in the C terminus. Sec24C did not bind to the tails from CLDN22 or CLDN23, which lacked the C‐terminal V (Figure A).…”

“…Four isoforms of Sec24, including Sec24A, Sec24B, Sec24C and Sec24D, play critical roles in COPII cargo sorting . Our previous studies have shown that many CLDN family proteins, including HCV co‐receptor CLDN1, depend on their own YV motif to associate with Sec24C and thus to be transported to the cell plasma membrane . CLDN12 does not have YV motif, and whether its transport is regulated by COPII vesicles is not clear.…”

Newly synthesized claudins but not occludin are added to the basal side of the tight junction

“…Together, these results suggest that beyond the cldn-PDZ binding motif interaction with ZO proteins, other proteins interacting with C-terminal residues, potentially components of the COPII sorting machinery (Yin et al. , 2017) and the ubiquitination pathway (Takahashi et al.…”

“…Some previous studies (Thanabalasuriar et al. , 2013; Yin et al. , 2017) have found that the YV motif at the carboxyl (C-) terminal end of some cldns is required for proper biosynthetic trafficking to the plasma membrane.…”

Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

“…Localization of CLDN1 at the cell surface to facilitate contact with CD81 is critical for HCV entry, and several factors that affect the localization of CLDN1 are important in the HCV entry process (Figure 1). Cell surface localization of CLDN1 (regulated by vesicular transport proteins such as Sec24C) is associated with enhanced HCV entry [120]. Tumor-associated calcium signal transducer 2 (TACSTD2) interacts with CLDN1 and OCLN, and regulates their localization through protein kinase C (PKC)-mediated phosphorylation [121].…”