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Review
. 2024 Jul 11;12(7):1405.
doi: 10.3390/microorganisms12071405.

Multiple Functions of Hepatitis E Virus ORF3

Fengyuan Jiao  1 , Yu Zhao  2 , Gengxu Zhou  1 , Chi Meng  1 , Lingjie Wang  1 , Shengping Wu  1 , Jixiang Li  1 , Liting Cao  1 , Bo Zhou  3 , Yichen Luo  1 , Hanwei Jiao  1
Affiliations
Review

Multiple Functions of Hepatitis E Virus ORF3

Fengyuan Jiao et al. Microorganisms. .

Abstract

Hepatitis E (Hepatitis E, HE) is an acute and chronic infectious hepatitis caused by hepatitis E virus (Hepatitis E Virus, HEV) infection, which is responsible for most acute hepatitis in the world and is a significant public health problem. The pathogen, HEV, has three Open Reading Frames (ORFs) ORF1, ORF2, and ORF3, each of which has a different function. Most of the current research is focused on ORF1 and ORF2, while the research on ORF3 is still relatively small. To provide more ideas for the study of HEV pathogenesis and the prevention and treatment of HE, this paper reviews the effects of ORF3 on the ERK pathway, growth factors, immune response, and virus release.

Keywords: HE; HEV; ORF3.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Homozygosity analysis of ORF3 in different genotypes. HEV 1(AAA45735.1), HEV2(AAA45731.1), HEV3(BAC44898.1), HEV 4(BAE02702.1), HEV5(BAJ77117.1), HEV 6(BAO31622.1), HEV7(AHY61297.1), HEV8(AOR52321.1). From the figure, it can be seen that HEV1 and HEV2 have the highest ORF3 homology and HEV7 and HEV8 also have high homology, whereas the highest dissimilarity is found in HEV5 and HEV7, followed by HEV6 and HEV7, which also have high dissimilarity.
Figure 2
Figure 2
(A)The hepatitis E virus genome RNA—genomic RNA and bicistronic subgenomic RNA. (B) Open reading frames. (C) Structure of ORF3 protein.
Figure 3
Figure 3
ORF3 maintains ERK activity. On the one hand, the ORF3 protein maintains ERK activity by binding to pyst1, thereby inhibiting the dephosphorylation of TXY. On the other hand, ORF3 directly binds to MPK3 to form a complex, which reduces ERK because of the dephosphorylation of MPK3 and thus comes to maintain ERK activity.
Figure 4
Figure 4
Pathways of NF-κB activity inhibition by ORF3. ORF3 directly promotes the degradation of TRADD to inhibit NF-κB activity, on the one hand, and inhibits NF-κB activity by directly inhibiting the dephosphorylation of IKKβ, on the other hand. In addition, IκBα activation needs to be facilitated by the dephosphorylation of IKKβ, so ORF3 not only directly inhibits IκBα activation, but also indirectly inhibits IκBα activation by inhibiting IKKβ activation.
Figure 5
Figure 5
ORF3 helps virus release. After the HEV invades the cell, it will first localize into the endosomes and, after a series of activities, the virus will delocalize for translation and the PXXP sequence of the ORF3 protein will bind to the TSG101 protein in the ESCRT system and translocate to the ESCRT. Then, the naked virus particles will interact with the translocated pORF3, which will cover the surface of the viral capsid and initiate virus release via the exosome pathway.
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