STAT2 is an Essential Adaptor in USP18-mediated Suppression of Type I Interferon Signaling

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2017 Feb 7

PMID 28165510

Citations 99

Authors

Kei-Ichiro Arimoto

Sara Lochte

Samuel A Stoner

Christoph Burkart

Yue Zhang

Sayuri Miyauchi

Stephan Wilmes

Jun-Bao Fan

Jurgen J Heinisch

Zhi Li

Ming Yan

Sandra Pellegrini

Frederic Colland

Jacob Piehler

Dong-Er Zhang

Affiliations

Soon will be listed here.

Abstract

Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK-STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. This mechanistic coupling of effector and negative-feedback functions of STAT2 may provide novel strategies for treatment of IFN-signaling-related human diseases.

Citing Articles

ISG15-Dependent Stabilisation of USP18 Is Necessary but Not Sufficient to Regulate Type I Interferon Signalling in Humans.

Vasou A, Nightingale K, Cetkovska V, Scheler J, Bamford C, Andrejeva J Eur J Immunol. 2025; 55(2):e202451651.

PMID: 39931755 PMC: 11811815. DOI: 10.1002/eji.202451651.

Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.

Davis G, Omole A, Jung Y, Rut W, Holewinski R, Suazo K Nat Commun. 2025; 16(1):957.

PMID: 39843430 PMC: 11754618. DOI: 10.1038/s41467-025-56336-5.

Infections in Inborn Errors of STATs.

Wang C, Freeman A Pathogens. 2024; 13(11).

PMID: 39599507 PMC: 11597637. DOI: 10.3390/pathogens13110955.

Suppression of SARS-CoV-2 nucleocapsid protein dimerization by ISGylation and its counteraction by viral PLpro.

Bang W, Kim J, Seo K, Lee J, Han J, Park D Front Microbiol. 2024; 15:1490944.

PMID: 39512937 PMC: 11540652. DOI: 10.3389/fmicb.2024.1490944.

ISG15 Drives Immune Pathology and Respiratory Failure during Systemic Lymphocytic Choriomeningitis Virus Infection.

Shaabani N, Zak J, Johnson J, Huang Z, Nguyen N, Lazar D J Immunol. 2024; 213(12):1811-1824.

PMID: 39495004 PMC: 11784630. DOI: 10.4049/jimmunol.2400042.

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