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

Shen, Qijun; Kumari, Sushila; Xu, Chaoyi; Jang, Sungwoo; Shi, Jiong; Burdick, Ryan C.; Levintov, Lev; Xiong, Qiancheng; Wu, Chunxiang; Devarkar, Swapnil C.; Tian, Taoran; Tripler, Therese; Hu, Yingxia; Yuan, Shuai; Temple, Joshua; Feng, Qingzhou; Lusk, C. Patrick; Aiken, Christopher; Engelman, Alan; Perilla, Juan R.; Pathak, Vinay K.; Lin, Chenxiang; Xiong, Yong

doi:10.1073/pnas.2202815120

Cited by 21 publications

(11 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The following day, the medium was replaced with fresh medium lacking aphidicolin. In experiments involving Nup153 depletion, cells were first transfected with control or Nup153-targeting siRNA duplexes as previously described 32 . Two days later, cells were replated for infection assays and for immunoblotting to confirm the knockdown efficiency.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

Deshpande,

Bryer,

Andino

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid1,2. Recent studies have shown that HIV- 1 cores enter the nucleus prior to capsid disassembly3–5. Interactions with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown. Here we show that the HIV-1 core is highly elastic and that this property is linked to nuclear entry and infectivity. Using atomic force microscopy-based approaches, we found that purified wild type cores rapidly returned to their normal conical morphology following a severe compression. Results from independently performed molecular dynamic simulations of the mature HIV-1 capsid also revealed its elastic property. Analysis of four HIV-1 capsid mutants that exhibit impaired nuclear entry revealed that the mutant viral cores are brittle. Suppressors of the mutants restored elasticity and rescued infectivity and nuclear entry. Elasticity was also reduced by treatment of cores with the capsid-targeting compound PF74 and the antiviral drug lenacapavir. Our results indicate that capsid elasticity is a fundamental property of the HIV-1 core that enables its passage through the nuclear pore complex, thereby facilitating infection. These results provide new insights into the mechanisms of HIV-1 nuclear entry and the antiviral mechanisms of HIV-1 capsid inhibitors.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Moreover, infection by these mutants was minimally affected by depletion of Nup153 (Fig. 1E) 32,33 . Purified cores from these mutants also exhibited increased stiffness.…”

mentioning

confidence: 97%

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

Deshpande,

Bryer,

Andino

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Viral proteins from HIV, SARS-CoV-2, Kaposi's sarcoma-associated herpesvirus, and vesicular stomatitis virus interact with and rearrange the nuclear pore complex to modulate nuclear import of transcription factors required for the anti-viral response 25,26,28,[52][53][54][55][56][57][58] . Similarly, C.t.…”

Section: Cebn Attenuates Stat1 Import Into the Nucleus Following Inte...mentioning

confidence: 99%

Global mapping of theChlamydia trachomatisconventional secreted effector – host interactome reveals CebN interacts with nucleoporins and Rae1 to impede STAT1 nuclear translocation

Steiert,

Andersen,

McCaslin

et al. 2024

Preprint

View full text Add to dashboard Cite

Chlamydia trachomatis (C.t.), the leading cause of bacterial sexually transmitted infections, employs a type III secretion system (T3SS) to translocate two classes of effectors, inclusion membrane proteins and conventional T3SS (cT3SS) effectors, into the host cell to counter host defense mechanisms. Here we employed three assays to directly evaluate secretion during infection, validating secretion for 23 cT3SS effectors. As bioinformatic analyses have been largely unrevealing, we conducted affinity purification-mass spectrometry to identify host targets and gain insights into the functions of these effectors, identifying high confidence interacting partners for 21 cT3SS effectors. We demonstrate that CebN localizes to the nuclear envelope in infected and bystander cells where it interacts with multiple nucleoporins and Rae1, blocking STAT1 nuclear import following IFN-γ stimulation. By building a cT3SS effector-host interactome, we have identified novel pathways that are targeted during bacterial infection and have begun to address how C.t. effectors combat cell autonomous immunity.

show abstract

“…HIV-1 can infect non-dividing cells by passing through nuclear pores and the CA protein has been identified as the driver for this nuclear entry [16,17]. This is partly mediated by direct interactions that CA makes with nucleoporins [18][19][20][21][22], however other cellular proteins, including transportins and cleavage and polyadenylation specificity factor 6 (CPSF6, also known as CFIm68) have also been implicated [23][24][25][26]. CPSF6 is a nuclear protein involved in alternative polyadenylation of pre-mRNA.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Capsid Rapidly Induces Long Lived CPSF6 Puncta in Non-dividing Cells but Similar Puncta Already Exist in Uninfected T-cells

Guedán,

Burley,

Caroe

et al. 2024

Preprint

View full text Add to dashboard Cite

The HIV-1 capsid (CA) protein forms the outer shell of the viral core that is released into the cytoplasm upon infection. CA binds various cellular proteins, including CPSF6, that directs HIV-1 integration into speckle associated domains in host chromatin. Upon HIV-1 infection, CPSF6 forms puncta in the nucleus. Here, we characterised these CPSF6 puncta further, in HeLa cells, T-cells and macrophages and confirm that integration and reverse transcription are not required for puncta formation. Indeed, we found that puncta formed very rapidly after infection, correlating with the time that CA entered the nucleus. In aphidicolin-treated HeLa cells and macrophages, puncta were detected for the length of the experiment, suggesting that puncta are only lost upon cell division. CA still co-localised with CPSF6 puncta at the latest time points, considerably after the peak of reverse transcription and integration. Intriguingly, the number of puncta induced in macrophages did not correlate with the MOI, or the total number of nuclear speckles present in each cell suggesting that CA/CPSF6 is only directed to a few nuclear speckles. Furthermore, we found that CPSF6 already co-localised with nuclear speckles in uninfected T-cells suggesting that HIV-1 promotes a natural behaviour of CPSF6.

show abstract

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

Cited by 21 publications

References 82 publications

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

Global mapping of theChlamydia trachomatisconventional secreted effector – host interactome reveals CebN interacts with nucleoporins and Rae1 to impede STAT1 nuclear translocation

HIV-1 Capsid Rapidly Induces Long Lived CPSF6 Puncta in Non-dividing Cells but Similar Puncta Already Exist in Uninfected T-cells

Contact Info

Product

Resources

About