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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Virology
Volume 15 - 2024 | doi: 10.3389/fmicb.2024.1456108

FGF21 Upregulation by Hepatitis C Virus via eIF2α-ATF4 Pathway: Implications for Interferon Signaling Suppression and TRIM31-Mediated TSC Degradation

Provisionally accepted
Liang Liu Liang Liu Masahiko Ito Masahiko Ito Satoshi Sakai Satoshi Sakai Jie Liu Jie Liu Kazuyoshi Ohta Kazuyoshi Ohta Kenji Saito Kenji Saito Kenji Nakashima Kenji Nakashima Shinya Satoh Shinya Satoh Alu Konno Alu Konno Tetsuro Suzuki Tetsuro Suzuki *
  • Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

The final, formatted version of the article will be published soon.

    Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases, known to induce endoplasmic reticulum (ER) stress, which alters cellular homeostasis and metabolic processes. While ER stress is implicated in HCV-related diseases, its precise role remains unclear. This study identifies fibroblast growth factor 21 (FGF21) as a key host factor significantly upregulated by HCV infection. Mechanistic analyses reveal that the activation of the FGF21 promoter by HCV is primarily mediated by the transcription factor ATF4, which is upregulated through the phosphorylation of eIF2α induced by ER stress. Additionally, CREBH activation further enhances ATF4 expression, contributing to increased FGF21 levels. TRIB3, upregulated by ATF4, acts as a negative regulator of FGF21 expression. The study also identifies FGF21-dependent upregulation of SOCS2 and TRIM31 in HCVinfected cells. SOCS2 contributes to the suppression of type 1 interferon signaling, aiding viral persistence, while TRIM31 promotes the degradation of the tumor suppressor protein TSC, activating the mTORC1 pathway and potentially promoting liver cell proliferation. These findings suggest that FGF21 upregulation in HCVinfected cells may play a role in both immune response regulation and cell proliferation, contributing to sustained viral infection and disease progression. Keywords：Hepatitis C virus; FGF21; ATF4; CREBH; TRIM31; SOCS2; ER stress.

    Keywords: Hepatitis C virus, FGF21, ATF4, CREBH, TRIM31, SOCS2, er stress

    Received: 28 Jun 2024; Accepted: 23 Jul 2024.

    Copyright: © 2024 Liu, Ito, Sakai, Liu, Ohta, Saito, Nakashima, Satoh, Konno and Suzuki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Tetsuro Suzuki, Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Shizuoka, Japan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.