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Regulation of Interferon Induction by the Ubiquitin-Like Modifier FAT10

by Mei Min Mah 1,†, Nicola Roverato 1,† and Marcus Groettrup 1,2,*
Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany
Biotechnology Institute Thurgau at the University of Konstanz, 8082 Kreuzlingen, Switzerland
Author to whom correspondence should be addressed.
These authors contributed equally to this article.
Biomolecules 2020, 10(6), 951;
Received: 29 April 2020 / Revised: 19 June 2020 / Accepted: 21 June 2020 / Published: 23 June 2020
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
The revelation that the human major histocompatibility complex (MHC) class I locus encodes a ubiquitin-like protein designated HLA-F adjacent transcript 10 (FAT10) or ubiquitin D (UBD) has attracted increasing attention to the function of this protein. Interestingly, the pro-inflammatory cytokines interferon (IFN)-γ and tumor necrosis factor (TNF) α synergize to strongly induce FAT10 expression, thereby suggesting a role of FAT10 in the immune response. Recent reports that FAT10 downregulates type I interferon production while it upregulates IFN-γ pose mechanistic questions on how FAT10 differentially regulates interferon induction. Several covalent and non-covalent binding partners of FAT10 involved in signal transduction pathways leading to IFN synthesis have been identified. After introducing FAT10, we review here recent insights into how FAT10 affects proteins in the interferon pathways, like the virus-responsive pattern recognition receptor RIG-I, the ubiquitin ligase ZNF598, and the deubiquitylating enzyme OTUB1. Moreover, we outline the consequences of FAT10 deficiency on interferon synthesis and viral expansion in mice and human cells. We discuss the need for covalent isopeptide linkage of FAT10 to the involved target proteins and the concomitant targeting for proteasomal degradation. After years of investigating the elusive biological functions of this fascinating ubiquitin-like modifier, we review the emerging evidence for a novel role of FAT10 in interferon regulation. View Full-Text
Keywords: interferon; ubiquitin; FAT10; signal transduction; RIG-I; influenza virus interferon; ubiquitin; FAT10; signal transduction; RIG-I; influenza virus
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MDPI and ACS Style

Mah, M.M.; Roverato, N.; Groettrup, M. Regulation of Interferon Induction by the Ubiquitin-Like Modifier FAT10. Biomolecules 2020, 10, 951.

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