TRIM22 Inhibits Influenza A Virus Infection by Targeting the Viral Nucleoprotein for Degradation

Pietro, Andrea Di; Kajaste‐Rudnitski, Anna; Oteiza, Alexandra; Nicora, Lucia; Towers, Greg J.; Mechti, Nadir; Vicenzi, Elisa

doi:10.1128/jvi.02548-12

Cited by 207 publications

(240 citation statements)

References 51 publications

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“…2) and that ubiquitination of RNP subunits is associated with increased synthesis of all viral RNA products. Our data are supported by prior reports showing ubiquitination of individual subunits of the RNP (12)(13)(14)26).…”

Section: Discussionsupporting

confidence: 92%

“…Ubiquitination mediates multiple cellular processes and is perhaps most commonly associated with proteasomal degradation (35). Ubiquitination had previously been associated with degradation of NP and free polymerase subunits (12,14,26). However, overexpression of WT or mutant forms of ubiquitin did not appreciably alter the steady-state levels of viral proteins (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…The E3 ligases TRIM22 and TRIM32 have been reported to be antiviral as they mediate proteasomal degradation of NP and PB1, respectively (14,26). Recent results have also shown an antiviral role for the ubiquitination and degradation of PB2 and PA, possibly associated with ADP ribosylation, another PTM these proteins undergo (12).…”

Section: Discussionmentioning

confidence: 99%

“…Polyubiquitination of NP by the E3 ligase TRIM22 directs its degradation and restricts virus replication (26). In contrast, monoubiquitination at K184 is hypothesized to enhance replication of the viral genome (13,26).…”

Section: Discussionmentioning

confidence: 99%

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Ubiquitination Upregulates Influenza Virus Polymerase Function

Kirui

Mondal

Mehle

2016

J Virol

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The influenza A virus polymerase plays an essential role in the virus life cycle, directing synthesis of viral mRNAs and genomes. It is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher-order ribonucleoprotein (RNP) complexes. The polymerase is regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including posttranslational modifications; however, the mechanisms are not fully understood. Here we demonstrate that ubiquitination plays an important role in stimulating polymerase activity. We show that all protein subunits in the RNP are ubiquitinated, but ubiquitination does not significantly alter protein levels. Instead, ubiquitination and an active proteasome enhance polymerase activity. Expression of ubiquitin upregulates polymerase function in a dose-dependent fashion, causing increased accumulation of viral RNA (vRNA), cRNA, and mRNA and enhanced viral gene expression during infection. Ubiquitin expression directly affects polymerase activity independent of nucleoprotein (NP) or ribonucleoprotein (RNP) assembly. Ubiquitination and the ubiquitin-proteasome pathway play key roles during multiple stages of influenza virus infection, and data presented here now demonstrate that these processes modulate viral polymerase activity independent of protein degradation. IMPORTANCEThe cellular ubiquitin-proteasome pathway impacts steps during the entire influenza virus life cycle. Ubiquitination suppresses replication by targeting viral proteins for degradation and stimulating innate antiviral signaling pathways. Ubiquitination also enhances replication by facilitating viral entry and virion disassembly. We identify here an addition proviral role of the ubiquitin-proteasome system, showing that all of the proteins in the viral replication machinery are subject to ubiquitination and this is crucial for optimal viral polymerase activity. Manipulation of the ubiquitin machinery for therapeutic benefit is therefore likely to disrupt the function of multiple viral proteins at stages throughout the course of infection.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ubiquitination Upregulates Influenza Virus Polymerase Function

Kirui

Mondal

Mehle

2016

J Virol

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“…TRIM22, also known as Staf-50, is a natural antiviral effector of HIV-1, 12 HBV 13 and influenza. 14 The dependence of the anti-viral function of TRIM22 on its ubiquitination function varies depending on the virus. 10,11 For example, TRIM22 inhibits influenza by targeting its nucleoprotein, but also inhibits the activity of the HBV core promoter not through ubiquitination.…”

Section: Introductionmentioning

confidence: 99%

Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A

et al. 2015

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TRIM22, a tripartite-motif (TRIM) protein, is upregulated upon interferon alpha (IFNa) administration to hepatitis C virus (HCV)-infected patients. However, the physiological role of TRIM22 upregulation remains unclear. Here, we describe a potential antiviral function of TRIM22's targeting of the HCV NS5A protein. NS5A is important for HCV replication and for resistance to IFNa therapy. During the first 24 h following the initiation of IFNa treatment, upregulation of TRIM22 in the peripheral blood mononuclear cells (PBMCs) of HCV patients correlated with a decrease in viral titer. This phenomenon was confirmed in the hepatocyte-derived cell line Huh-7, which is highly permissive for HCV infection. TRIM22 over-expression inhibited HCV replication, and Small interfering RNA (siRNA)-mediated knockdown of TRIM22 diminished IFNa-induced anti-HCV function. Furthermore, we determined that TRIM22 ubiquitinates NS5A in a concentration-dependent manner. In summary, our results suggest that TRIM22 upregulation is associated with HCV decline during IFNa treatment and plays an important role in controlling HCV replication in vitro.

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iTRAQ‐based proteomic and bioinformatic characterization of human mast cells upon infection by the influenza A virus strains H1N1 and H5N1

Zhang

Huo

et al. 2019

FEBS Letters

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Mast cells can support the replication of influenza A virus, although how this occurs is poorly understood. In the present study, using quantitative MS, we analyzed the proteome of human mast cells infected with different influenza A virus strains at 12 h post‐infection. Forty‐one differentially expressed proteins were identified in human mast cells upon infection by the virulent H5N1 (A/Chicken/Henan/1/04) virus compared to the seasonal H1N1 (A/WSN/33) virus. Bioinformatic analyses confirmed that H1N1 significantly regulates the RNA degradation pathway via up‐regulation of CCR4‐NOT transcription complex subunit 4, whereas apoptosis could be suppressed by H5N1 via down‐regulation of the tumor protein p53 signaling pathway with P ≤ 0.05 at 12 h post‐infection. The hypoxia‐inducible factor‐1 signaling pathway of human mast cells is more susceptible to infection by H5N1 than by H1N1 virus.

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TRIM22 Inhibits Influenza A Virus Infection by Targeting the Viral Nucleoprotein for Degradation

Cited by 207 publications

References 51 publications

Ubiquitination Upregulates Influenza Virus Polymerase Function

Ubiquitination Upregulates Influenza Virus Polymerase Function

Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A

iTRAQ‐based proteomic and bioinformatic characterization of human mast cells upon infection by the influenza A virus strains H1N1 and H5N1

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