Viperin

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RSAD2
Identifiers
AliasesRSAD2, 2510004L01Rik, cig33, cig5, vig1, radical S-adenosyl methionine domain containing 2, Viperin Protein, Viperin
External IDsOMIM: 607810 MGI: 1929628 HomoloGene: 10969 GeneCards: RSAD2
Orthologs
SpeciesHumanMouse
Entrez

91543

58185

Ensembl

ENSG00000134321

ENSMUSG00000020641

UniProt

Q8WXG1

Q8CBB9

RefSeq (mRNA)

NM_080657

NM_021384

RefSeq (protein)

NP_542388

NP_067359

Location (UCSC)Chr 2: 6.87 – 6.9 MbChr 12: 26.49 – 26.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Radical S-adenosyl methionine domain-containing protein 2 is a protein that in humans is encoded by the RSAD2 gene. RSAD2 is a multifunctional protein in viral processes that is an interferon stimulated gene.[5] It has been reported that viperin could be induced by either IFN-dependent or IFN-independent pathways and certain viruses may use viperin to increase their infectivity.[6][7]

The protein was previous called Virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (Viperin). The name viperin has been rectified due to inappropriate use of it to describe homologous prokaryotic enzymes producing nucleotide analogues.[8] The enzymes across all domains of life are renamed SAM-dependent nucleotide dehydratase (SAND) using NC-IUBMB recommendations.[8]

Function

Viperin is an interferon-stimulated gene whose expression inhibits many DNA and RNA viruses including CHIKV, HCMV, HCV, DENV, WNV, SINV, influenza, and HIV.[6] Initially identified as an IFN-γ induced antiviral protein in human cytomegalovirus (HCMV) infected macrophages, it was reported that viperin could be induced by HCMV glycoprotein B in fibroblasts, but inhibits HCMV viral infection and down-regulates viral structural proteins. The reason why virus protein would induce viperin against itself is still not clear; however, the viral induced redistribution of viperin may reflect the mechanism of virus evading its antiviral activities.[9] Viperin may also be induced and interact with HCMV viral proteins and relocate to mitochondria in HCMV viral infected cells to enhance viral infectivity by disrupting cellular metabolism.[10]

Viperin is a radical SAM enzyme which is capable of producing the chain terminator ddhCTP (3ʹ-deoxy-3′,4ʹdidehydro-CTP), which inhibits the viral RNA dependent RNA polymerase (RdRp).[11] ddhCTP also appears to abolish metabolism of amino acids and mitochondrial respiration.[12]

In the inhibition of influenza virus budding and release, viperin is suggested to disrupt the lipid rafts on the cell's plasma membrane by binding to and decreasing the enzyme activities of farnesyl diphosphate synthase (FPPS), an essential enzyme in isoprenoid biosynthesis pathway.[13] Viperin was suggested to inhibit the viral replication of HCV via its interaction with host hVAP-33 and viral NS5A and disrupting the formation of the replication complex.[14]

Structure

Human viperin is a single polypeptide of 361 amino acids with a predicted molecular weight of 42 kDa. The N-terminal 42 amino acids of viperin forms amphipathic alpha-helix, which is relatively less conserved in different species and has a minor effect on the antiviral activity of viperin. The N-terminal domain of viperin is required for its localization to the ER and lipid droplets.[15] Amino acids 77-209 of viperin constitute the radical S-adenosyl methionine (SAM) domain, containing four conserved motifs. Motif 1 has three conserved cysteine residues, CxxCxxC, which is the Fe-S binding motif and also essential for antiviral activity.[10] The C-terminal 218-361 amino acids of viperin are highly conserved in different species and essential for viperin dimerization. The C-terminal tail appears to be critical for the antiviral activities against HCV since a C-terminal flag tagged of viperin lost its antiviral activity.[16]

When viperin is bound to SAM and Cytidine triphosphate (CTP) or uridine triphosphate (UTP) is used as a substrate, different kinetic parameters are achieved.[17] It is predicted that the CTP substrate binds much more tightly with viperin because of the low Km value of the substrate. However, the overall structure of both UTP- and CTP-bound compounds are similar. The difference being that the uracil moiety is less effective then the cytosine moiety at binding and ordering turns A and B. Nucleotide-free viperin contains a (βα)6 partial barrel and has a disordered N-terminal extension and a partially ordered C-terminal extension.[18] When the C-terminal tail is ordered, a six-residue α-helix, an eight-residue P-loop (that binds the γ-phosphate of CTP), and a 310-helix are revealed.

Cellular localization

Viperin is normally localized to the endoplasmic reticulum (ER) via its N-terminal domain, and also localized to lipid droplet, which are derived from the ER.[15] However, it is also found in mitochondria in the HCMV infected fibroblasts.[10]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000134321 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020641 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Seo JY, Yaneva R, Cresswell P (December 2011). "Viperin: a multifunctional, interferon-inducible protein that regulates virus replication". Cell Host & Microbe. 10 (6): 534–9. doi:10.1016/j.chom.2011.11.004. PMC 3246677. PMID 22177558.
  6. ^ a b Mattijssen S, Pruijn GJ (May 2012). "Viperin, a key player in the antiviral response". Microbes and Infection. 14 (5): 419–26. doi:10.1016/j.micinf.2011.11.015. hdl:2066/94161. PMID 22182524.
  7. ^ Helbig KJ, Beard MR (March 2014). "The role of viperin in the innate antiviral response". Journal of Molecular Biology. Antiviral Innate Immunity (Part II). 426 (6): 1210–9. doi:10.1016/j.jmb.2013.10.019. hdl:2440/94032. PMID 24157441.
  8. ^ a b Ji Y, Wei L, Da A, Stark H, Hagedoorn PL, Ciofi-Baffoni S, et al. (21 October 2022). "Radical-SAM dependent nucleotide dehydratase (SAND), rectification of the names of an ancient iron-sulfur enzyme using NC-IUBMB recommendations". Frontiers in Molecular Biosciences. 9: 1032220. doi:10.3389/fmolb.2022.1032220. PMC 9642334. PMID 36387278.
  9. ^ Chin KC, Cresswell P (December 2001). "Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus". Proceedings of the National Academy of Sciences of the United States of America. 98 (26): 15125–15130. Bibcode:2001PNAS...9815125C. doi:10.1073/pnas.011593298. PMC 64994. PMID 11752458.
  10. ^ a b c Seo JY, Yaneva R, Hinson ER, Cresswell P (May 2011). "Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity". Science. 332 (6033): 1093–1097. Bibcode:2011Sci...332.1093S. doi:10.1126/science.1202007. PMID 21527675. S2CID 22293459.
  11. ^ Gizzi AS, Grove TL, Arnold JJ, Jose J, Jangra RK, Garforth SJ, et al. (June 2018). "A naturally occurring antiviral ribonucleotide encoded by the human genome". Nature. 558 (7711). Springer Science and Business Media LLC: 610–614. Bibcode:2018Natur.558..610G. doi:10.1038/s41586-018-0238-4. PMC 6026066. PMID 29925952.
  12. ^ Honarmand Ebrahimi K, Vowles J, Browne C, McCullagh J, James WS (May 2020). "ddhCTP produced by the radical-SAM activity of RSAD2 (viperin) inhibits the NAD+ -dependent activity of enzymes to modulate metabolism". FEBS Letters. 594 (10): 1631–1644. doi:10.1002/1873-3468.13778. PMID 32232843.
  13. ^ Wang X, Hinson ER, Cresswell P (August 2007). "The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts". Cell Host & Microbe. 2 (2): 96–105. doi:10.1016/j.chom.2007.06.009. PMID 18005724.
  14. ^ Helbig KJ, Eyre NS, Yip E, Narayana S, Li K, Fiches G, et al. (November 2011). "The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A". Hepatology. 54 (5): 1506–1517. doi:10.1002/hep.24542. PMC 3207276. PMID 22045669.
  15. ^ a b Hinson ER, Cresswell P (December 2009). "The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic alpha-helix". Proceedings of the National Academy of Sciences of the United States of America. 106 (48): 20452–20457. Bibcode:2009PNAS..10620452H. doi:10.1073/pnas.0911679106. PMC 2778571. PMID 19920176.
  16. ^ Jiang D, Guo H, Xu C, Chang J, Gu B, Wang L, et al. (February 2008). "Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus". Journal of Virology. 82 (4): 1665–1678. doi:10.1128/JVI.02113-07. PMC 2258705. PMID 18077728.
  17. ^ Fenwick MK, Su D, Dong M, Lin H, Ealick SE (February 2020). "Structural Basis of the Substrate Selectivity of Viperin". Biochemistry. 59 (5). American Chemical Society (ACS): 652–662. doi:10.1021/acs.biochem.9b00741. PMC 7920147. PMID 31917549.
  18. ^ Fenwick MK, Li Y, Cresswell P, Modis Y, Ealick SE (June 2017). "Structural studies of viperin, an antiviral radical SAM enzyme". Proceedings of the National Academy of Sciences of the United States of America. 114 (26). Proceedings of the National Academy of Sciences: 6806–6811. Bibcode:2017PNAS..114.6806F. doi:10.1073/pnas.1705402114. PMC 5495270. PMID 28607080.

External links

Retrieved from "https://mdwiki.org/wiki/Viperin"