TRIM26 is a critical host factor for HCV replication and contributes to host tropism

Abstract

Hepatitis C virus (HCV) remains a major human pathogen that requires better understanding of virus-host interactions. In this study, we performed a genome-wide CRISPR-Cas9 screening and identified TRIM26, an E3 ligase, as a critical HCV host factor. Deficiency of TRIM26 specifically impairs HCV genome replication. Mechanistic studies showed that TRIM26 interacts with HCV-encoded NS5B protein and mediates its K27-linked ubiquitination at residue K51, and thus promotes the NS5B-NS5A interaction. Moreover, mouse TRIM26 does not support HCV replication because of its unique six–amino acid insert that prevents its interaction with NS5B. Ectopic expression of human TRIM26 in a mouse hepatoma cell line that has been reconstituted with other essential HCV host factors promotes HCV infection. In conclusion, we identified TRIM26 as a host factor for HCV replication and a new determinant of host tropism. These results shed light on HCV-host interactions and may facilitate the development of an HCV animal model.

Targeting Aryl Hydrocarbon Receptor Signaling Enhances Type I Interferon-Independent Resistance to Herpes Simplex Virus

“…Since viral genomes have a limited coding capacity, DNA/RNA viruses often hijack cellular factors to promote their proliferation in host cells. It was reported that TRIM26, an E3 ligase, was a critical host factor for hepatitis C virus (HCV) replication and contributed to host tropism ( 20 ). There is also evidence that HSV-1 hijacks cofilin to facilitate virus entry into neuronal cells ( 21 ).…”

Gene editing and its applications in biomedicine

“…Typical examples include screens to identify coding genes conferring resistance to a drug, toxin, pathogen, or immune cells (Guo et al, 2022;Liang et al, 2021;Peng et al, 2015;Ren et al, 2015;Shalem et al, 2014;Zhao et al, 2019;Zhou et al, 2014;Zhu et al, 2021). In a positive screen, the majority of cells are depleted under strong selection conditions, and only a few cells with a protective phenotype expand.…”

Emerging Roles of MHC Class I Region-Encoded E3 Ubiquitin Ligases in Innate Immunity

“…However, another study reported that TRIM26 actually enhanced innate immunity against RNA viruses, by recruiting NEMO to facilitate the interaction between TBK1 and MAVS ( 66 ). Furthermore, a genome-wide CRISPR-Cas9 screening identified TRIM26 as a critical HCV host factor, where it mediates K27-linked ubiquitination of HCV-encoded NS5B protein, enhances the interaction between NS5B-NS5A, and ultimately promotes HCV genome replication ( 67 ). Thus, as a key E3 ubiquitin ligase, TRIM26 plays multiple roles through catalyzing the conjugation of multiple ubiquitin chains to variety of substrates.…”