USP18

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

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. and the dissociation of the cytokine-receptor complex. This process requires STAT2 to traffic USP18 to the receptor 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. 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.

Stabilization

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

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.

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

References

References

1. "Entrez Gene: USP18 ubiquitin specific peptidase 18".
2. (December 2018). "USP18 - a multifunctional component in the interferon response". Bioscience Reports.
3. (June 2006). "UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity". The EMBO Journal.
4. (2011). "USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response". PLOS ONE.
5. (May 2015). "Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling". The Journal of Cell Biology.
6. (March 2017). "STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling". Nature Structural & Molecular Biology.
7. (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.
8. (December 2019). "Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2". Science Immunology.
9. (March 2002). "UBP43 (USP18) specifically removes ISG15 from conjugated proteins". The Journal of Biological Chemistry.
10. (February 2017). "ISG15: In Sickness and in Health". Trends in Immunology.
11. (January 2015). "Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation". Nature.
12. (March 2020). "Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models". The Journal of Infectious Diseases.
13. (May 2016). "ISG15 deficiency and increased viral resistance in humans but not mice". Nature Communications.
14. (2018-10-15). "USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1". Journal of Virology.
15. (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.
16. (2021-09-22). "Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses". Frontiers in Immunology.
17. (2021-09-09). "The Landscape of IFN/ISG Signaling in HIV-1-Infected Macrophages and Its Possible Role in the HIV-1 Latency". Cells.
18. (2021-04-26). "People with HIV-1 Demonstrate Type 1 Interferon Refractoriness Associated with Upregulated USP18". Journal of Virology.
19. (June 2016). "Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome". The Journal of Experimental Medicine.
20. (January 2020). "JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency". The New England Journal of Medicine.