USP18

Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a type I interferon receptor repressor and an isopeptidase. In humans, it is encoded by the USP18 gene.[5] USP18 is induced by the immune response to type I and III interferons, and serves as a negative regulator of type I interferon, but not type III interferon. Loss of USP18 results in increased responsiveness to type I interferons and life-threatening autoinflammatory disease in humans due to the negative regulatory function of USP18 in interferon signal transduction. Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove ISG15 conjugates from a broad range of protein substrates, a process known as deISGylation.[5]

USP18
Identifiers
AliasesUSP18, ISG43, UBP43, ubiquitin specific peptidase 18, PTORCH2
External IDsOMIM: 607057 MGI: 1344364 HomoloGene: 8047 GeneCards: USP18
Gene location (Human)
Chr.Chromosome 22 (human)[1]
Band22q11.21Start18,150,170 bp[1]
End18,177,397 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

11274

24110

Ensembl

ENSG00000184979

ENSMUSG00000030107

UniProt

Q9UMW8

Q9WTV6

RefSeq (mRNA)

NM_017414

NM_011909

RefSeq (protein)

NP_059110

NP_036039

Location (UCSC)Chr 22: 18.15 – 18.18 MbChr 6: 121.25 – 121.27 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

The USP18 gene consists of 11 exons that encode a 43 kDa protein. The USP18 protein adopts the characteristic hand-like structure of ubiquitin-specific-proteases (USPs), which consists of a finger, palm and thumb domain. At the interface of the palm and thumb domain lies the catalytic site composed of the cysteine protease triad (cysteine, a histidine and an aspartate or asparagine).[6] The C-terminus of USP18 is primarily responsible for negative regulation of interferon-I signaling.[7]

Function

Following its induction by type I interferons (IFN-Is), USP18 carries out three functional interactions:

Regulation of IFN-I signaling

USP18 inhibits IFN-I signaling by disrupting the receptor complex and the subsequent JAK-STAT signaling pathway. USP18 binds the IFN-receptor 2 subunit (IFNAR2), leading to the displacement of Janus kinase 1.[7][8] and the dissociation of the cytokine-receptor complex.[9] This process requires STAT2 to traffic USP18 to the receptor [10][11][12] These events terminate signaling and draw cells into a refractory state with diminished sensitivity to future stimulation.[8]

deISGylation

Using the isopeptidase domain, USP18 specifically deconjugates ISG15 (interferon-stimulated gene 15) from tagged proteins.[13] This reaction is termed deISGylation, as the initial conjugation of ISG15 to newly-synthesized proteins is termed ISGylation, a process akin to ubiquitination. However, unlike other de-ubiquitinating enzymes, USP18 is specific to ISG15, and exhibits no cross-reactivity with ubiquitin. The consequences of ISGylation and deISGylation are incompletely understood.[14]

Stabilization

USP18 is stabilized by ISG15, but independently of the ubiquitin-like conjugation.[15] Without ISG15-mediated stabilization, USP18 is degraded at the proteasome. This relationship exists in human, canine and porcine USP18/ISG15,[16] but is absent in murine systems.[17]

Clinical significance

USP18-deficiency is a very rare primary immunodeficiency caused by mutations of the USP18 gene. The inheritance is autosomal recessive. The clinical disease presents in the perinatal period with life-threatening autoinflammation that mimics TORCH infections, but in the absence of infection. The severe inflammation results from a failure to regulate type I IFN activity, and is therefore considered a type I interferonopathy. This syndrome was initially described to result in death within weeks of birth.[18] Fortunately, this previously-lethal condition was recently demonstrated to be curable with a Janus kinase inhibitor and intensive supportive care.[19]

References
  1. GRCh38: Ensembl release 89: ENSG00000184979 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000030107 - 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. "Entrez Gene: USP18 ubiquitin specific peptidase 18".
  6. Basters A, Knobeloch KP, Fritz G (December 2018). "USP18 - a multifunctional component in the interferon response". Bioscience Reports. 38 (6). doi:10.1042/BSR20180250. PMC 6240716. PMID 30126853.
  7. Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, et al. (June 2006). "UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity". The EMBO Journal. 25 (11): 2358–67. doi:10.1038/sj.emboj.7601149. PMC 1478183. PMID 16710296.
  8. François-Newton V, Magno de Freitas Almeida G, Payelle-Brogard B, Monneron D, Pichard-Garcia L, Piehler J, et al. (2011). "USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response". PLOS ONE. 6 (7): e22200. Bibcode:2011PLoSO...622200F. doi:10.1371/journal.pone.0022200. PMC 3136508. PMID 21779393.
  9. Wilmes S, Beutel O, Li Z, Francois-Newton V, Richter CP, Janning D, et al. (May 2015). "Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling". The Journal of Cell Biology. 209 (4): 579–93. doi:10.1083/jcb.201412049. PMC 4442803. PMID 26008745.
  10. Arimoto KI, Löchte S, Stoner SA, Burkart C, Zhang Y, Miyauchi S, et al. (March 2017). "STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling". Nature Structural & Molecular Biology. 24 (3): 279–289. doi:10.1038/nsmb.3378. PMC 5365074. PMID 28165510.
  11. Gruber C, Martin-Fernandez M, Ailal F, Qiu X, Taft J, Altman J, et al. (May 2020). "Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy". The Journal of Experimental Medicine. 217 (5). doi:10.1084/jem.20192319. PMC 7201920. PMID 32092142.
  12. Duncan CJ, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, et al. (December 2019). "STAT2". Science Immunology. 4 (42). doi:10.1126/sciimmunol.aav7501. hdl:20.500.11820/3908eba0-5d5c-404d-b79f-08e6bd93b61d. PMID 31836668.
  13. Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE (March 2002). "UBP43 (USP18) specifically removes ISG15 from conjugated proteins". The Journal of Biological Chemistry. 277 (12): 9976–81. doi:10.1074/jbc.M109078200. PMID 11788588.
  14. Hermann M, Bogunovic D (February 2017). "ISG15: In Sickness and in Health". Trends in Immunology. 38 (2): 79–93. doi:10.1016/j.it.2016.11.001. PMID 27887993.
  15. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, et al. (January 2015). "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation". Nature. 517 (7532): 89–93. Bibcode:2015Natur.517...89Z. doi:10.1038/nature13801. PMC 4303590. PMID 25307056.
  16. Qiu X, Taft J, Bogunovic D (March 2020). "Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models". The Journal of Infectious Diseases. 221 (6): 890–894. doi:10.1093/infdis/jiz549. PMC 7050986. PMID 31637432.
  17. Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F, et al. (May 2016). "ISG15 deficiency and increased viral resistance in humans but not mice". Nature Communications. 7: 11496. Bibcode:2016NatCo...711496S. doi:10.1038/ncomms11496. PMC 4873964. PMID 27193971.
  18. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, et al. (June 2016). "Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome". The Journal of Experimental Medicine. 213 (7): 1163–74. doi:10.1084/jem.20151529. PMC 4925017. PMID 27325888.
  19. Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, Le Voyer T, Alghamdi M, et al. (January 2020). "JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency". The New England Journal of Medicine. 382 (3): 256–265. doi:10.1056/NEJMoa1905633. PMC 7155173. PMID 31940699.

Further reading
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