The HIV capsid mimics karyopherin engagement of FG-nucleoporins

Nature, Год журнала: 2024, Номер unknown

Опубликована: Янв. 24, 2024

Abstract HIV can infect non-dividing cells because the viral capsid overcome selective barrier of nuclear pore complex and deliver genome directly into nucleus 1,2 . Remarkably, intact is more than 1,000 times larger size limit prescribed by diffusion 3 This in central channel composed intrinsically disordered nucleoporin domains enriched phenylalanine–glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins their bound cargoes solubilize this phase to drive nucleocytoplasmic transport 4 By performing an vitro dissection complex, we show that a pocket on surface similarly interacts with motifs from multiple nucleoporins interaction licences capsids penetrate FG-nucleoporin condensates. karyopherin mimicry model addresses key conceptual challenge for role entry offers explanation as how exogenous entity much any known cargo may be able non-destructively breach envelope.

Язык: Английский

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HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor

Nature, Год журнала: 2024, Номер 626(8000), С. 843 - 851

Опубликована: Янв. 24, 2024

Abstract HIV-1 infection requires nuclear entry of the viral genome. Previous evidence suggests that this proceeds through pore complexes (NPCs), with 120 × 60 nm capsid squeezing an approximately 60-nm-wide central channel 1 and crossing permeability barrier NPC. This can be described as FG phase 2 is assembled from cohesively interacting phenylalanine–glycine (FG) repeats 3 selectively permeable to cargo captured by transport receptors (NTRs). Here we show assemblies target NPCs efficiently in NTR-independent manner bind directly several types repeats, including barrier-forming cohesive repeats. Like NTRs, readily partitions into vitro serve NPC mimic excludes much smaller inert probes such mCherry. Indeed, protein greatly enhanced assembly, which also allows encapsulated clients enter. Thus, our data indicate behaves like NTR, its interior serving a container. Because capsid-coating trans -acting NTRs would increase diameter 10 or more, suggest ‘self-translocating’ undermines size restrictions imposed scaffold, thereby bypassing otherwise effective infection.

Язык: Английский

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HIV-1 capsid shape, orientation, and entropic elasticity regulate translocation into the nuclear pore complex

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(4)

Опубликована: Янв. 19, 2024

Nuclear import and uncoating of the viral capsid are critical steps in HIV-1 life cycle that serve to transport release genomic material into nucleus. Viral core involves translocating at nuclear pore complex (NPC). Notably, central channel NPC appears often accommodate allow passage intact capsid, though mechanistic details process remain be fully understood. Here, we investigate molecular interactions operate concert between regulate translocation through channel. To this end, develop a “bottom-up” coarse-grained (CG) model human from recently released cryo-electron tomography structure then construct composite membrane-embedded CG models. We find successful cytoplasmic side is contingent on compatibility morphology dimension proper orientation approach side. The dynamics driven by maximizing contacts phenylalanine-glycine nucleoporins capsid. For docked capsids, structural analysis reveals correlated striated patterns lattice disorder likely related intrinsic elasticity. Uncondensed inside augments overall Our results suggest “elasticity” can also aid adapt stress structurally during translocation.

Язык: Английский

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Structure and function of retroviral integrase

Nature Reviews Microbiology, Год журнала: 2021, Номер 20(1), С. 20 - 34

Опубликована: Июль 9, 2021

Язык: Английский

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Nuclear Capsid Uncoating and Reverse Transcription of HIV-1

Annual Review of Virology, Год журнала: 2022, Номер 9(1), С. 261 - 284

Опубликована: Июнь 15, 2022

After cell entry, human immunodeficiency virus type 1 (HIV-1) replication involves reverse transcription of the RNA genome, nuclear import subviral complex without envelope breakdown, and integration viral complementary DNA into host genome. Here, we discuss recent evidence indicating that completion genome uncoating occur in nucleus rather than cytoplasm, as previously thought, suggest a testable model for uncoating. Multiple studies indicated cone-shaped capsid, which encases proteins, not only serves reaction container shield from innate immune sensors but also may constitute elusive HIV-1 factor. Rupture capsid be triggered by transcription, yet-unknown factors, or physical damage, it appears to close temporal spatial association with process.

Язык: Английский

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Evasion of cGAS and TRIM5 defines pandemic HIV

Nature Microbiology, Год журнала: 2022, Номер 7(11), С. 1762 - 1776

Опубликована: Окт. 26, 2022

Abstract Of the 13 known independent zoonoses of simian immunodeficiency viruses to humans, only one, leading human virus (HIV) type 1(M) has become pandemic, causing over 80 million infections. To understand specific features associated with pandemic human-to-human HIV spread, we compared replication HIV-1(M) non-pandemic HIV-(O) and HIV-2 strains in myeloid cell models. We found that lineages replicate less well than owing activation cGAS TRIM5-mediated antiviral responses. applied phylogenetic X-ray crystallography structural analyses identify differences between capsids. genetic reversal two amino acid adaptations enables TRIM5, innate immune propose a model which parental lineage evolved capsid prevents TRIM5 triggering, thereby allowing silent cells. hypothesize this adaptation promotes spread through avoidance response activation.

Язык: Английский

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Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 6, 2022

Abstract Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage biologically relevant mature lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid binding to lattices. Structural studies revealed multivalent CPSF6 assembly mediated by LCR-LCR interactions, which are templated FG a subset hydrophobic pockets positioned along adjoining hexamers. In infected cells, LCR-mediated cores essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied the complex potently impair inside nucleus without displacing tightly bound cofactor from virus cores. These results establish previously undescribed mechanisms antiviral action.

Язык: Английский

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Modeling HIV-1 nuclear entry with nucleoporin-gated DNA-origami channels

Nature Structural & Molecular Biology, Год журнала: 2023, Номер 30(4), С. 425 - 435

Опубликована: Фев. 20, 2023

Язык: Английский

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The capsid lattice engages a bipartite NUP153 motif to mediate nuclear entry of HIV-1 cores

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(13)

Опубликована: Март 21, 2023

Increasing evidence has suggested that the HIV-1 capsid enters nucleus in a largely assembled, intact form. However, not much is known about how cone-shaped interacts with nucleoporins (NUPs) nuclear pore for crossing complex. Here, we elucidate NUP153 binds by engaging assembled protein (CA) lattice. A bipartite motif containing both canonical and noncanonical interaction modules was identified at C-terminal tail region of NUP153. The cargo-targeting phenylalanine-glycine (FG) engaged CA hexamer. By contrast, previously unidentified triple-arginine (RRR) targeted tri-hexamer interface capsid. infection studies indicated FG- RRR-motifs were important import cores. Moreover, presence stabilized tubular assemblies vitro. Our results provide molecular-level mechanistic contributes to entry into nucleus.

Язык: Английский

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The HIV-1 capsid core is an opportunistic nuclear import receptor

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июнь 24, 2023

Abstract The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process. HIV-1 capsid (CA), the chief structural component viral core, a critical determinant in transport virus. interactions with NPCs are dependent on CA, which makes direct contact nucleoporins (Nups). Here we identify Nup35, Nup153, POM121 coordinately support entry. For Nup35 POM121, dependence was cyclophilin A (CypA) interaction CA. Mutation CA or removal soluble host factors changed NPC. make via regions containing phenylalanine glycine motifs (FG-motifs). Collectively, these findings provide additional evidence that core functions as receptor (NTR) exploits modulate NPC requirements during invasion.

Язык: Английский

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