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Investigations into the molecular mechanism of FAT10-mediated antiviral type-I interferon response

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2024

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Open Access-Veröffentlichung
Open Access Green
Core Facility der Universität Konstanz
Bioimaging Centre, Flow Cytometry Centre, Proteomics Centre

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3. Juli 2026

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Dissertation
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Zusammenfassung

HLA-F adjacent transcript 10 (FAT10) is a ubiquitin-like modifier (ULM) that consists of two ubiquitin-like domains (UBL) connected with a flexible linker. The C-terminal diglycine motif of FAT10 facilitates its covalent conjugation to the substrates using E1 activating, E2 conjugating, and E3 ligase enzymes. FAT10 is expressed in the organs of the immune system and synergistic stimulation with proinflammatory cytokines TNF/IFNγ can induce its expression in almost every cell type. FAT10 is involved in various biological processes such as antigen presentation, apoptosis, autophagy, innate immune response, cell cycle regulation and cancer. In this study, we investigated the role of FAT10 in regulating type-I interferon secretion upon influenza A virus (IAV) infection. We show that FAT10 gets phosphorylated upon IAV infection and TNF treatment by the inhibitor of nuclear factor kappa B kinase-β (IKKβ). Phosphorylated FAT10 interacts with OTUB1 with a higher affinity and activates its deubiquitinase activity, which catalyzes the deubiquitination of TRAF3, resulting in the downregulation of type-I interferon production. TRIM21 is an E3 ligase whose expression is induced upon virus infection. TRIM21 regulates antiviral type-I interferon signaling in a positive feedback manner. We investigated the cross-talk between FAT10 and TRIM21 during the antiviral type-I interferon response. We observed that FAT10 covalently conjugates to TRIM21 and targets it for proteasomal degradation. TRIM21- FAT10 conjugation is catalyzed by the E1 activating enzyme UBA6 and the E2 conjugating enzyme USE1. The C-terminal diglycine motif of FAT10 and the coiled-coil and PRYSPRY domains of TRIM21 are important for TRIM21-FAT10 conjugation. Moreover, upon IAV infection and in the presence of FAT10 the bulk ubiquitination of TRIM21 is reduced. Taken together, we show that FAT10-mediated inhibition of TRIM21 results in the downregulation of type-I interferon secretion upon IAV infection. In the third project of this thesis, we investigated stress transmission in social groups of mice. We analyzed behavioral, physiological, and immunological responses in chronic restraint stress (CRS) and socially transmitted stress (TS) mice. This study provides insights into the contagion nature of chronic stress and improves our understanding of the implications of stress transmission in the social dynamics of animal groups.

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570 Biowissenschaften, Biologie

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FAT10, TRIM21, Ubiquitination, Type I interferon, Influenza A virus

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ISO 690SAXENA, Kritika, 2024. Investigations into the molecular mechanism of FAT10-mediated antiviral type-I interferon response [Dissertation]. Konstanz: Universität Konstanz
BibTex
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  year={2024},
  title={Investigations into the molecular mechanism of FAT10-mediated antiviral type-I interferon response},
  author={Saxena, Kritika},
  address={Konstanz},
  school={Universität Konstanz}
}
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    <dcterms:abstract>HLA-F adjacent transcript 10 (FAT10) is a ubiquitin-like modifier (ULM) that consists of two 
ubiquitin-like domains (UBL) connected with a flexible linker. The C-terminal diglycine motif of 
FAT10 facilitates its covalent conjugation to the substrates using E1 activating, E2 conjugating, 
and E3 ligase enzymes. FAT10 is expressed in the organs of the immune system and synergistic 
stimulation with proinflammatory cytokines TNF/IFNγ can induce its expression in almost every 
cell type. FAT10 is involved in various biological processes such as antigen presentation, 
apoptosis, autophagy, innate immune response, cell cycle regulation and cancer.
In this study, we investigated the role of FAT10 in regulating type-I interferon secretion upon 
influenza A virus (IAV) infection. We show that FAT10 gets phosphorylated upon IAV infection 
and TNF treatment by the inhibitor of nuclear factor kappa B kinase-β (IKKβ). Phosphorylated 
FAT10 interacts with OTUB1 with a higher affinity and activates its deubiquitinase activity, which 
catalyzes the deubiquitination of TRAF3, resulting in the downregulation of type-I interferon 
production.
TRIM21 is an E3 ligase whose expression is induced upon virus infection. TRIM21 regulates 
antiviral type-I interferon signaling in a positive feedback manner. We investigated the cross-talk 
between FAT10 and TRIM21 during the antiviral type-I interferon response. We observed that 
FAT10 covalently conjugates to TRIM21 and targets it for proteasomal degradation. TRIM21-
FAT10 conjugation is catalyzed by the E1 activating enzyme UBA6 and the E2 conjugating 
enzyme USE1. The C-terminal diglycine motif of FAT10 and the coiled-coil and PRYSPRY 
domains of TRIM21 are important for TRIM21-FAT10 conjugation. Moreover, upon IAV 
infection and in the presence of FAT10 the bulk ubiquitination of TRIM21 is reduced. Taken 
together, we show that FAT10-mediated inhibition of TRIM21 results in the downregulation of 
type-I interferon secretion upon IAV infection. 
In the third project of this thesis, we investigated stress transmission in social groups of mice. We 
analyzed behavioral, physiological, and immunological responses in chronic restraint stress (CRS)
and socially transmitted stress (TS) mice. This study provides insights into the contagion nature of 
chronic stress and improves our understanding of the implications of stress transmission in the 
social dynamics of animal groups.</dcterms:abstract>
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Prüfungsdatum der Dissertation

June 24, 2024
Hochschulschriftenvermerk
Konstanz, Univ., Diss., 2024
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