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Review
. 2022 May 6:13:835344.
doi: 10.3389/fmicb.2022.835344. eCollection 2022.

Dual-Role Ubiquitination Regulation Shuttling the Entire Life Cycle of the Flaviviridae

Dongjie Cai  1 , Lingli Liu  1 , Bin Tian  2 , Xingxin Fu  1 , Qiyuan Yang  1 , Jie Chen  1 , Yilin Zhang  1   3 , Jing Fang  4 , Liuhong Shen  1 , Ya Wang  1 , Liping Gou  1 , Zhicai Zuo  1
Affiliations
Review

Dual-Role Ubiquitination Regulation Shuttling the Entire Life Cycle of the Flaviviridae

Dongjie Cai et al. Front Microbiol. .

Abstract

Ubiquitination is a reversible protein post-translational modification that regulates various pivotal physiological and pathological processes in all eukaryotes. Recently, the antiviral immune response is enhanced by the regulation of ubiquitination. Intriguingly, Flaviviridae viruses can ingeniously hijack the ubiquitination system to help them survive, which has become a hot topic among worldwide researchers. The Flaviviridae family members, such as HCV and CSFV, can cause serious diseases of humans and animals around the world. The multiple roles of ubiquitination involved in the life cycle of Flaviviridae family would open new sight for future development of antiviral tactic. Here, we discuss recent advances with regard to functional roles of ubiquitination and some ubiquitin-like modifications in the life cycle of Flaviviridae infection, shedding new light on the antiviral mechanism research and therapeutic drug development.

Keywords: CSFV; Flaviviridae; HCV; TRIM proteins; antiviral immunity; ubiquitin system.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The ubiquitin system. (A) Activation: ubiquitin is activated and bound to E1 with ATP as an energy source. (B) Conjugation: ubiquitin is conjugated to E2. (C) Substrate targeting: substrates are targeted by E3. (D) Ligation: ubiquitin is ligated to the substrate. (E) Deubiquitinating: ubiquitin is recycled by the deubiquitinating enzymes.
Figure 2
Figure 2
Genome structure of Flaviviridae family. The Flaviviridae genome is composed of a 5′-terminal non-coding region (NCR) and a 3′-terminal NCR, and a single long ORF (open reading frame) encoding the polyprotein. The polyprotein is cleaved by viral and host proteases to produce about 10–12 mature proteins. Grey represents viral structural proteins, while brown represents non-structural proteins.
Figure 3
Figure 3
The life cycle of Flaviviridae. (A) Attachment: E envelope protein of viral particles interacts with the cell receptor. (B) Entry: virus enters the host cell by clathrin-mediated endocytosis. (C) Internalization: the low pH environment in the endosome triggers a conformational change of the E glycoprotein, and then the viral envelope fuses with the endosomal membrane. Following the nucleocapsid of virus is released into the cytoplasm. (D) Replication: the genome is transported into cytoplasm, then the viral RNA and proteins are synthesized in the endoplasmic reticulum. (E) Assembly: the viral particle is assembled in the adjacent endoplasmic reticulum, then immature virus particles egress (blue triangle, envelope proteins). (F) Release: mature virions (green triangle, envelope proteins) are released after the Golgi apparatus modification.
Figure 4
Figure 4
Ubiquitin in viral attachment, entry and internalization. (A) Ubiquitination of E protein: ubiquitination of TRIM7-mediated K63-linked on the K38 residue of the E protein promotes the effective adhesion of ZIKV to host receptor; USP38 binds to ZIKV envelope (E) protein and attenuates K48-linked and K63-linked polyubiquitination; LAMR1 binds with E protein to attenuate the ubiquitination of E protein. (B) Ubiquitination of receptor TIM-1: the ubiquitination of TIM-1 promotes the endocytosis of DENV. (C) Ubiquitination in virus internalization: MG132 and lactacystin (proteasome inhibitors) reduced the productive virions internalization of Japanese encephalitis virus (JEV). The action of Pyr41 (E1 inhibitor) confirmed that ubiquitination is necessary for the uncoating process of DENV and YFV.
Figure 5
Figure 5
Ubiquitin in the replication complex of Flaviviridae. 3 (NS3): TRIM69 ubiquitinates virus NS3 protein in the K11-linked way, causing NS3 degradation to inhibit DENV replication. TRIM5α inhibits replication and promotes the ubiquitination of its K48-linked and proteasome degradation by binding to Flaviviruses virus protease NS2B/3. But, NS3 is modified by the K27-linked polyubiquitin to promote virus replication. 4B (NS4B): PRNF114 mediates the polyubiquitin of K27-linked NS4B, which degrades NS4B, through the proteasome pathway and then inhibits CSFV replication. 5A (NS5A): TRIM22 and SPSB2 directly target NS5A, and degrade it through ubiquitination to inhibit HCV replication. UBE2S and TRIM14 degrade NS5A protein through Lys11-linked and Lys48-linked proteasome-dependent pathways. SUMOylation improves the stability of NS5A protein by inhibiting ubiquitination, thus promoting the interaction between NS5A and NS5B protein. NS5A is the active target of ISGylation, but the roles of ISGylation remain obscure. 5B (NS5B): TRIM26-mediated K27-linked ubiquitination of NS5B at residue K51 enhances the interaction between NS5B and NS5A, thereby promoting the replication of the HCV. Fbw7 can interact with NS5B and degrade NS5B by K48-linked ubiquitination. (A) Replication complex of HCV and CSFV: PRNF114 mediates the polyubiquitin of K27-linked NS4B, which degrades NS4B through the proteasome pathway and then inhibits CSFV replication; TRIM22 and SPSB2 directly target NS5A, and degrade it through ubiquitination to inhibit HCV replication; UBE2S and TRIM14 degrade NS5A protein through Lys11-linked and Lys48-linked proteasome-dependent pathways. SUMOylation improves the stability of NS5A protein by inhibiting ubiquitination to promote the interaction between NS5A and NS5B protein; NS5A is the active target of ISGylation, however, whether the role of ISGylation is to promote or inhibit is controversial; TRIM26-mediated K27-linked ubiquitination of NS5B at residue K51 enhances the interaction between NS5B and NS5A to facilitate HCV replication; Fbw7 can interact with NS5B and degrade NS5B by K48-linked ubiquitination. Black arrows, promoting replication complexes; red arrows, inhibiting replication complexes. (B) Replication complex of Flaviviruses: TRIM69 ubiquitinates virus NS3 protein in the K11-linked way, causing NS3 degradation to inhibit DENV replication; the other studies show that NS3 is modified only by the K27-linked polyubiquitin to facilitate virus replication, and which linkages are needed to be discussed further; TRIM5α inhibits virus replication and promotes the ubiquitination of its K48-linked and proteasome degradation by binding to NS2B/3 (Flaviviruses protease); interferon stimulating gene 15 (ISG15) and sumo contribute to the stabilization of NS5 and promote virus replication.
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References

    1. Abe T., Minami N., Bawono R. G., Matsui C., Deng L., Fukuhara T., et al. . (2020). ISGylation of hepatitis C virus NS5A protein promotes viral RNA replication via recruitment of Cyclophilin A. J. Virol. 94:e00532-20. doi: 10.1128/JVI.00532-20, PMID: - DOI - PMC - PubMed
    1. Assenberg R., Mastrangelo E., Walter T. S., Verma A., Milani M., Owens R. J., et al. . (2009). Crystal structure of a novel conformational state of the flavivirus NS3 protein: implications for polyprotein processing and viral replication. J. Virol. 83, 12895–12906. doi: 10.1128/JVI.00942-09, PMID: - DOI - PMC - PubMed
    1. Barouch-Bentov R., Neveu G., Xiao F., Beer M., Bekerman E., Schor S., et al. . (2016). Hepatitis C virus proteins interact with the endosomal sorting complex required for transport (ESCRT) machinery via ubiquitination to facilitate viral envelopment. MBio 7, e01456–e01516. doi: 10.1128/mBio.01456-16, PMID: - DOI - PMC - PubMed
    1. Barrows N. J., Campos R. K., Liao K. C., Prasanth K. R., Soto-Acosta R., Yeh S. C., et al. . (2018). Biochemistry and molecular biology of Flaviviruses. Chem. Rev. 118, 4448–4482. doi: 10.1021/acs.chemrev.7b00719, PMID: - DOI - PMC - PubMed
    1. Bartenschlager R., Penin F., Lohmann V., Andre P. (2011). Assembly of infectious hepatitis C virus particles. Trends Microbiol. 19, 95–103. doi: 10.1016/j.tim.2010.11.005, PMID: - DOI - PubMed

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