MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6

Xie, Linlin; Chen, Lang; Zhong, Chaojie; Yu, Ting; Zhao, Jing‐Tai; Wang, Meirong; Xiong, Hairong; Zeng, Yan; Wang, Jianhua; Hu, Haitao; Hou, Wei; Feng, Yong

doi:10.1186/s12977-020-00524-2

Cited by 23 publications

(18 citation statements)

References 50 publications

(97 reference statements)

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“…Such factors can be described as soluble or membrane-bound, with the latter proteins serving as components of the cell’s NPC ( Figure 1 ; also see below). Soluble CA-binding proteins that play roles in HIV-1 RTC nuclear import include CypA [ 83 ], TNPO1 [ 76 ], BICD2 [ 65 , 66 ], and cleavage and polyadenylation specificity factor 6 (CPSF6) [ 17 , 18 , 71 , 84 ].…”

Section: Ca Interactions During Nuclear Importmentioning

confidence: 99%

“…Plausibly, RTCs become bottlenecked in the nuclear basket in Nup153-depleted cells, increasing the propensity for the PIC to target nearby LADs for integration, though this has not been formally tested. MxB interacts with various Nups including Nup214 [ 120 ] and Nup358 [ 84 ]. MxB restriction may retarget PICs from integrating into gene dense regions by inhibiting the Nup358-CA interaction [ 84 ].…”

Section: Ca Interactions In Integration Targetingmentioning

confidence: 99%

“…MxB interacts with various Nups including Nup214 [ 120 ] and Nup358 [ 84 ]. MxB restriction may retarget PICs from integrating into gene dense regions by inhibiting the Nup358-CA interaction [ 84 ]. Interestingly, disruption of the CA-CypA interaction increased HIV-1 integration targeting of gene-dense regions of chromatin [ 104 ] and, predictably, SPAD regions.…”

Section: Ca Interactions In Integration Targetingmentioning

confidence: 99%

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HIV Capsid and Integration Targeting

Engelman

2021

Viruses

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Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of viral genomes to daughter cells. Before integration can occur, retroviral reverse transcription complexes (RTCs) must access the nuclear environment where the chromosomes reside. Retroviral integration is non-random, with different types of virus-host interactions impacting where in the host chromatin integration takes place. Lentiviruses such as HIV efficiently infect interphase cells because their RTCs have evolved to usurp cellular nuclear import transport mechanisms, and research over the past decade has revealed specific interactions between the HIV capsid protein and nucleoporin (Nup) proteins such as Nup358 and Nup153. The interaction of HIV capsid with cleavage and polyadenylation specificity factor 6 (CPSF6), which is a component of the cellular cleavage and polyadenylation complex, helps to dictate nuclear import as well as post-nuclear RTC invasion. In the absence of the capsid-CPSF6 interaction, RTCs are precluded from reaching nuclear speckles and gene-rich regions of chromatin known as speckle-associated domains, and instead mis-target lamina-associated domains out at the nuclear periphery. Highlighting this area of research, small molecules that inhibit capsid-host interactions important for integration site targeting are highly potent antiviral compounds.

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Section: Ca Interactions During Nuclear Importmentioning

confidence: 99%

Section: Ca Interactions In Integration Targetingmentioning

confidence: 99%

Section: Ca Interactions In Integration Targetingmentioning

confidence: 99%

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HIV Capsid and Integration Targeting

Engelman

2021

Viruses

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“…The binding of capsid to MxB is facilitated by MxB dimerization since inhibition of dimerization precludes the binding of MxB to CA [ 113 , 115 ]. In addition to the stabilizing effect of MxB, it appears to repress nuclear import by NUP358 through a CPSF6 dependent pathway [ 116 ]. It was also discovered that naturally occurring CA variants might render HIV-1 MxB-resistant while maintaining viral infectivity and interferon induction escape [ 117 ].…”

Section: Capsid Is a Target Of Host Cell Restriction Factorsmentioning

confidence: 99%

Structure, Function, and Interactions of the HIV-1 Capsid Protein

Rossi

Meuser

Cunanan

et al. 2021

Life

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The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

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“…Moreover, the longer isoform localizes to the nuclear periphery while the shorter isoform is cytoplasmic as is MX1 [ 222 ]. These findings, together with the demonstration that MX2 inhibition is after reverse transcription, focused attention on nuclear import and led to the findings that several nuclear import proteins interact with MX2 and are involved in MX2 inhibition of HIV-1 [ 223 , 224 , 225 ].…”

Section: Retroviral Restriction Factorsmentioning

confidence: 99%

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

Boso

Kozak

2020

Microorganisms

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The evolutionary conflict between retroviruses and their vertebrate hosts over millions of years has led to the emergence of cellular innate immune proteins termed restriction factors as well as their viral antagonists. Evidence accumulated in the last two decades has substantially increased our understanding of the elaborate mechanisms utilized by these restriction factors to inhibit retroviral replication, mechanisms that either directly block viral proteins or interfere with the cellular pathways hijacked by the viruses. Analyses of these complex interactions describe patterns of accelerated evolution for these restriction factors as well as the acquisition and evolution of their virus-encoded antagonists. Evidence is also mounting that many restriction factors identified for their inhibition of specific retroviruses have broader antiviral activity against additional retroviruses as well as against other viruses, and that exposure to these multiple virus challenges has shaped their adaptive evolution. In this review, we provide an overview of the restriction factors that interfere with different steps of the retroviral life cycle, describing their mechanisms of action, adaptive evolution, viral targets and the viral antagonists that evolved to counter these factors.

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MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6

Cited by 23 publications

References 50 publications

HIV Capsid and Integration Targeting

HIV Capsid and Integration Targeting

Structure, Function, and Interactions of the HIV-1 Capsid Protein

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

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