USP18 explained

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.[1] 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.[1]

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).[2] The C-terminus of USP18 is primarily responsible for negative regulation of interferon-I signaling.[3]

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.[4] and the dissociation of the cytokine-receptor complex.[5] This process requires STAT2 to traffic USP18 to the receptor [6] [7] [8] These events terminate signaling and draw cells into a refractory state with diminished sensitivity to future stimulation.

deISGylation

Using the isopeptidase domain, USP18 specifically deconjugates ISG15 (interferon-stimulated gene 15) from tagged proteins.[9] 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.[10]

Stabilization

USP18 is stabilized by ISG15, but independently of the ubiquitin-like conjugation.[11] Without ISG15-mediated stabilization, USP18 is degraded at the proteasome. This relationship exists in human, canine and porcine USP18/ISG15,[12] but is absent in murine systems.[13]

Promoting factor of HIV infection

Macrophages and dendritic cells are usually the first point of contact with pathogens, including lentiviruses. Host restriction factors, including SAMHD1, mediate the innate immune response against these viruses. However, HIV-1 has evolved to circumvent the innate immune response and establishes disseminated infection. It was reported that human USP18 is a novel factor potentially contributing to HIV replication by blocking the antiviral function of p21 in differentiated human myeloid cells. USP18 downregulates p21 protein expression, which correlates with upregulated intracellular dNTP levels and the antiviral inactive form of SAMHD1. Depletion of USP18 stabilizes p21 protein expression, which correlates with dephosphorylated SAMHD1 and a block to HIV-1 replication.[14] [15] [16] [17] [18]

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.[19] Fortunately, this previously lethal condition was recently demonstrated to be curable with a Janus kinase inhibitor and intensive supportive care.[20]

Further reading

Notes and References

  1. Web site: Entrez Gene: USP18 ubiquitin specific peptidase 18.
  2. Basters A, Knobeloch KP, Fritz G . USP18 - a multifunctional component in the interferon response . Bioscience Reports . 38 . 6 . December 2018 . 30126853 . 10.1042/BSR20180250 . 6240716 .
  3. Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, Shuai K, Zhang DE . 6 . UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity . The EMBO Journal . 25 . 11 . 2358–67 . June 2006 . 16710296 . 10.1038/sj.emboj.7601149 . 1478183 .
  4. François-Newton V, Magno de Freitas Almeida G, Payelle-Brogard B, Monneron D, Pichard-Garcia L, Piehler J, Pellegrini S, Uzé G . 6 . USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response . PLOS ONE . 2011 . 6 . 7 . e22200 . 21779393 . 10.1371/journal.pone.0022200 . 3136508 . 2011PLoSO...622200F . free .
  5. Wilmes S, Beutel O, Li Z, Francois-Newton V, Richter CP, Janning D, Kroll C, Hanhart P, Hötte K, You C, Uzé G, Pellegrini S, Piehler J . 6 . Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling . The Journal of Cell Biology . 209 . 4 . 579–93 . May 2015 . 26008745 . 10.1083/jcb.201412049 . 4442803 .
  6. Arimoto KI, Löchte S, Stoner SA, Burkart C, Zhang Y, Miyauchi S, Wilmes S, Fan JB, Heinisch JJ, Li Z, Yan M, Pellegrini S, Colland F, Piehler J, Zhang DE . 6 . STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling . Nature Structural & Molecular Biology . 24 . 3 . 279–289 . March 2017 . 28165510 . 10.1038/nsmb.3378 . 5365074 .
  7. Gruber C, Martin-Fernandez M, Ailal F, Qiu X, Taft J, Altman J, Rosain J, Buta S, Bousfiha A, Casanova JL, Bustamante J, Bogunovic D . 6 . 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 . May 2020 . 32092142 . 10.1084/jem.20192319 . 7201920 .
  8. Duncan CJ, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, Lovell SC, Shuttleworth VG, Brocklebank V, Corner B, Skelton AJ, Bondet V, Coxhead J, Duffy D, Fourrage C, Livingston JH, Pavaine J, Cheesman E, Bitetti S, Grainger A, Acres M, Innes BA, Mikulasova A, Sun R, Hussain R, Wright R, Wynn R, Zarhrate M, Zeef LA, Wood K, Hughes SM, Harris CL, Engelhardt KR, Crow YJ, Randall RE, Kavanagh D, Hambleton S, Briggs TA . 6 . Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 . Science Immunology . 4 . 42 . December 2019 . eaav7501 . 31836668 . 10.1126/sciimmunol.aav7501 . 7115903 . 20.500.11820/3908eba0-5d5c-404d-b79f-08e6bd93b61d . free .
  9. Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE . UBP43 (USP18) specifically removes ISG15 from conjugated proteins . The Journal of Biological Chemistry . 277 . 12 . 9976–81 . March 2002 . 11788588 . 10.1074/jbc.M109078200 . free .
  10. Hermann M, Bogunovic D . ISG15: In Sickness and in Health . Trends in Immunology . 38 . 2 . 79–93 . February 2017 . 27887993 . 10.1016/j.it.2016.11.001 .
  11. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, Volpi S, Li Z, Sanal O, Mansouri D, Tezcan I, Rice GI, Chen C, Mansouri N, Mahdaviani SA, Itan Y, Boisson B, Okada S, Zeng L, Wang X, Jiang H, Liu W, Han T, Liu D, Ma T, Wang B, Liu M, Liu JY, Wang QK, Yalnizoglu D, Radoshevich L, Uzé G, Gros P, Rozenberg F, Zhang SY, Jouanguy E, Bustamante J, García-Sastre A, Abel L, Lebon P, Notarangelo LD, Crow YJ, Boisson-Dupuis S, Casanova JL, Pellegrini S . 6 . Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation . Nature . 517 . 7532 . 89–93 . January 2015 . 25307056 . 10.1038/nature13801 . 4303590 . 2015Natur.517...89Z .
  12. Qiu X, Taft J, Bogunovic D . Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models . The Journal of Infectious Diseases . 221 . 6 . 890–894 . March 2020 . 31637432 . 10.1093/infdis/jiz549 . 7050986 .
  13. Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F, Rubino E, Gardner TJ, Wedeking T, Hermann M, Duehr J, Sanal O, Tezcan I, Mansouri N, Tabarsi P, Mansouri D, Francois-Newton V, Daussy CF, Rodriguez MR, Lenschow DJ, Freiberg AN, Tortorella D, Piehler J, Lee B, García-Sastre A, Pellegrini S, Bogunovic D . 6 . ISG15 deficiency and increased viral resistance in humans but not mice . Nature Communications . 7 . 11496 . May 2016 . 27193971 . 10.1038/ncomms11496 . 4873964 . 2016NatCo...711496S .
  14. Osei Kuffour. Edmund. Schott. Kerstin. Jaguva Vasudevan. Ananda Ayyappan. Holler. Jessica. Schulz. Wolfgang A.. Lang. Philipp A.. Lang. Karl S.. Kim. Baek. Häussinger. Dieter. König. Renate. Münk. Carsten. 2018-10-15. Sundquist. Wesley I.. USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1. Journal of Virology. en. 92. 20. 10.1128/JVI.00592-18. 0022-538X. 6158439. 30068654.
  15. Chintala. Kumaraswami. Mohareer. Krishnaveni. Banerjee. Sharmistha. 2021-07-29. Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms. Frontiers in Immunology. 12. 716927. 10.3389/fimmu.2021.716927. 1664-3224. 8358655. 34394123. free.
  16. Gao. Wenying. Rui. Yajuan. Li. Guangquan. Zhai. Chenyang. Su. Jiaming. Liu. Han. Zheng. Wenwen. Zheng. Baisong. Zhang. Wenyan. Yang. Yongjun. Hua. Shucheng. 2021-09-22. Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses. Frontiers in Immunology. 12. 740713. 10.3389/fimmu.2021.740713. 1664-3224. 8492978. 34630422. free.
  17. Rojas. Masyelly. Luz-Crawford. Patricia. Soto-Rifo. Ricardo. Reyes-Cerpa. Sebastián. Toro-Ascuy. Daniela. 2021-09-09. The Landscape of IFN/ISG Signaling in HIV-1-Infected Macrophages and Its Possible Role in the HIV-1 Latency. Cells. en. 10. 9. 2378. 10.3390/cells10092378. 2073-4409. 8467246. 34572027. free.
  18. Sugawara. Sho. El-Diwany. Ramy. Cohen. Laura K.. Rousseau. Kimberly E.. Williams. Christopher Y. K.. Veenhuis. Rebecca T.. Mehta. Shruti H.. Blankson. Joel N.. Thomas. David L.. Cox. Andrea L.. Balagopal. Ashwin. 2021-04-26. Simon. Viviana. People with HIV-1 Demonstrate Type 1 Interferon Refractoriness Associated with Upregulated USP18. Journal of Virology. en. 95. 10. 10.1128/JVI.01777-20. 0022-538X. 8139647. 33658340.
  19. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, Li Z, van Unen L, Heijsman D, Goldmann T, Lequin MH, Kros JM, Stam W, Hermann M, Willemsen R, Brouwer RW, Van IJcken WF, Martin-Fernandez M, de Coo I, Dudink J, de Vries FA, Bertoli Avella A, Prinz M, Crow YJ, Verheijen FW, Pellegrini S, Bogunovic D, Mancini GM . 6 . Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome . The Journal of Experimental Medicine . 213 . 7 . 1163–74 . June 2016 . 27325888 . 10.1084/jem.20151529 . 4925017 .
  20. Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, Le Voyer T, Alghamdi M, Qiu X, Alotaibi N, Alkahtani A, Buta S, Jouanguy E, Al-Eyadhy A, Gruber C, Hasan GM, Bashiri FA, Halwani R, Hassan HH, Al-Muhsen S, Alkhamis N, Alsum Z, Casanova JL, Bustamante J, Bogunovic D, Alangari AA . 6 . JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency . The New England Journal of Medicine . 382 . 3 . 256–265 . January 2020 . 31940699 . 10.1056/NEJMoa1905633 . 7155173 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "USP18".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.