Viral Appropriation: Laying Claim to Host Nuclear Transport Machinery

Tessier, Tanner M.; Dodge, Mackenzie J.; Prusinkiewicz, Martin; Mymryk, Joe S.

doi:10.3390/cells8060559

Cited by 23 publications

(22 citation statements)

References 195 publications

(232 reference statements)

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“…The stimulus and mechanistic details of virus uncoating remain largely concealed. Virus infection in eukaryotic cells often depends on the nuclear transport machinery ( Cohen et al, 2011 ; Matreyek and Engelman, 2013 ; Tessier et al, 2019 ). Recent studies have shown a direct role of Trn1 in virus uncoating ( Fernandez et al, 2019 ; Miyake et al, 2019 ; Carlon-Andres et al, 2020 ; Yamauchi, 2020 ).…”

Section: Moonlighting Functions Of Transportin-1mentioning

confidence: 99%

Transportin-1: A Nuclear Import Receptor with Moonlighting Functions

Mboukou

Rajendra

Kleinová

et al. 2021

Front. Mol. Biosci.

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Transportin-1 (Trn1), also known as karyopherin-β2 (Kapβ2), is probably the best-characterized nuclear import receptor of the karyopherin-β family after Importin-β, but certain aspects of its functions in cells are still puzzling or are just recently emerging. Since the initial identification of Trn1 as the nuclear import receptor of hnRNP A1 ∼25 years ago, several molecular and structural studies have unveiled and refined our understanding of Trn1-mediated nuclear import. In particular, the understanding at a molecular level of the NLS recognition by Trn1 made a decisive step forward with the identification of a new class of NLSs called PY-NLSs, which constitute the best-characterized substrates of Trn1. Besides PY-NLSs, many Trn1 cargoes harbour NLSs that do not resemble the archetypical PY-NLS, which complicates the global understanding of cargo recognition by Trn1. Although PY-NLS recognition is well established and supported by several structures, the recognition of non-PY-NLSs by Trn1 is far less understood, but recent reports have started to shed light on the recognition of this type of NLSs. Aside from its principal and long-established activity as a nuclear import receptor, Trn1 was shown more recently to moonlight outside nuclear import. Trn1 has for instance been caught in participating in virus uncoating, ciliary transport and in modulating the phase separation properties of aggregation-prone proteins. Here, we focus on the structural and functional aspects of Trn1-mediated nuclear import, as well as on the moonlighting activities of Trn1.

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Section: Moonlighting Functions Of Transportin-1mentioning

confidence: 99%

Transportin-1: A Nuclear Import Receptor with Moonlighting Functions

Mboukou

Rajendra

Kleinová

et al. 2021

Front. Mol. Biosci.

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“…By coevolving with eukaryotic hosts, viral pathogens have developed diverse mechanisms to usurp this important and highly coordinated pathway. These include mimicry of cellular NLSs by viral proteins and manipulation of these host factors at the molecular level (9).…”

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confidence: 99%

“…Through a highthroughput drug-screening approach, ivermectin was also identified as a general inhibitor of Imp-␣/␤1-mediated nuclear import (31). Several recent studies have explored ivermectin as a means of abrogating nuclear localization of viral proteins and as an inhibitor of viral replication (9). Several RNA viruses, including human immunodeficiency virus (HIV), dengue virus (DENV), and Hendra virus (HeV), were potently inhibited in vitro by ivermectin (32)(33)(34).…”

mentioning

confidence: 99%

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

King

Tessier

Dodge

et al. 2020

J Virol

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Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease, however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin's broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1 mediated nuclear import. IMPORTANCE Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms, however individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro. This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of Imp-α to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.

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“…That the INM STING pool can mobilize to translocate to the ONM through the peripheral channels of the NPC may reflect a backup mechanism to signal IIR responses using the peripheral NPC channels when viruses inhibit central channel transport. Viruses often target the central channel of the NPCs to either block transport or to usurp it so that virus transcripts are preferentially transported over host-directed transport 71,72,73,74 , but the peripheral channels are normally used for membrane protein transport 38,42,43,75 so that STING as a multi-spanning transmembrane protein could bypass this block to signal IIR. This does not preclude the well-established STING signaling cascades from the ER/Golgi compartment normally using the central channel of the NPC -indeed IRF3 is known to translocate through the NPC central channel 76,77 , but our findings of increased STING mobility and nucleo-cytoplasmic shuttling during IIR through the peripheral NPC channels suggest that STING may provide a backup system for activating IIR when central channel transport is disrupted.…”

Section: Discussionmentioning

confidence: 99%

STING Nuclear Partners Contribute to Innate Immune Signalling Responses

Dixon

Malik

Heras

et al. 2020

Preprint

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STING and cGAS initiate innate immune responses (IIR) by recognizing cytoplasmic pathogen dsDNA and activating signaling cascades from the ER; however, another less investigated pool of STING resides in the nuclear envelope. We find that STING in the inner nuclear membrane increases mobility and changes localization upon IIR activation both from dsDNA and poly(I:C) stimuli. We next identified nuclear partners of STING from isolated nuclear envelopes. These include several known nuclear membrane proteins, bromodomain and epigenetic enzymes, and RNA- or DNA-binding proteins. Strikingly, 17 of these DNA and RNA-binding STING partners are known to bind direct partners of the IRF3/7 transcription factors that are central drivers of IIR. We find that several of these STING partners —SYNCRIP, Men1, Ddx5, snRNP70, RPS27a, Aatf— can contribute to IIR activation and SYNCRIP can moreover protect against influenza A virus infection. These data suggest that the many roles identified for STING likely reflect its interactions with multiple RNA and DNA-binding proteins that also function in IIR.

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Viral Appropriation: Laying Claim to Host Nuclear Transport Machinery

Cited by 23 publications

References 195 publications

Transportin-1: A Nuclear Import Receptor with Moonlighting Functions

Transportin-1: A Nuclear Import Receptor with Moonlighting Functions

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

STING Nuclear Partners Contribute to Innate Immune Signalling Responses

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