Nuclear warfare: pathogen manipulation of the nuclear pore complex and nuclear functions

Abstract

Viruses and bacteria exploit the nuclear pore complex (NPC) and host nuclear functions to bypass cellular barriers and manipulate essential processes. Viruses frequently engage directly with NPC components, such as nucleoporins, to enable genome import and evade immune defenses. In contrast, bacterial pathogens rely on secreted effector proteins to disrupt nuclear transport and reprogram host transcription. These strategies reflect a remarkable evolutionary convergence, with both types of pathogens targeting the NPC and nuclear functions to promote infection. This minireview explores the overlapping and unique mechanisms by which pathogens hijack the host nucleus, shedding light on their roles in disease and potential avenues for therapeutic intervention.

Keywords: NPC; bacteria; effector; nucleus; virus.

Fig 1

Viruses and bacteria target the nuclear pore complex. (A) Schematic depicting the nuclear pore complex, highlighting the core elements, including localization of various NUPs. (B) HSV, EBV, HIV, VSV, KSHV, SARS-CoV-2, Chlamydia trachomatis, and Orientia tsutsugamushi all target the NPC. Left to right: HSV proteins pUL36 and pUL25 target RANBP2 and NUP214, respectively, to allow for uptake of the viral genome into the nucleus. O. tsutsugamushi proteins Ank6 and Ank1 are translocated to the nucleus through interactions with importin β1. In the nucleus, these proteins interact with exportin 1 to export p65, preventing NF-κB-mediated transcription. EBV protein BGLF4 phosphorylates NUP153 and NUP62, inhibiting the import of host proteins but allowing for the import of EBV proteins. The HIV capsid protein interacts with multiple NPC proteins, including RANBP2, NUP214, NUP88, NUP62, NUP98, and NUP153. These interactions allow for the translocation of the viral core and subsequent release of viral RNA in the nucleus. C. trachomatis-secreted effector CT584 interacts with various NUPs, including NUP214 and NUP153, as well as mRNA export factor Rae1. CT584 is able to impede import of STAT1 into the nucleus following immune stimulation. The M protein of VSV, ORF10 of KSHV, and ORF6 of SARS-CoV-2 all interact with the Rae1–NUP98 complex to block mRNA export, while ORF6 also prevents host protein import.

Fig 2

Pathogens target the nuclear lamin, transcriptional regulators, histones, and DNA. (A) EBV, HSV, Chlamydia abortus, and Chlamydia psittaci all target the nuclear lamin. Left to right: C. abortus protein CAB063 binds to lamin A. The consequence of this interaction is unknown. HSV-1 infection leads to a redistribution of laminal proteins. Viral proteins pUL31 and pUL34 alter the localization of LAP2. Further, host PKC is recruited, and along with viral proteins pUS3 and ICP34.5, lamin and LAP proteins are phosphorylated, resulting in disruption of the lamin layer. This allows for nuclear egress. C. psittaci protein SINC is translocated into the nucleus through interactions with importin β. Inside the nucleus, SINC interacts with the laminal protein emerin. The physiological relevance of this interaction is yet to be determined. The EBV protein BGLF4 interacts with lamin A, resulting in phosphorylation of lamin A and redistribution of the nuclear lamina to help facilitate nuclear egress. (B) IAV, MeV, Coxiella burnetii, Legionella pneumophila, and Shigella flexneri target transcriptional regulators. Left to right: C. burnetii protein AnkG interacts with DDX21. This interaction inhibits the canonical function of DDX21, which would normally release pTEFb from the 7SK snRNP complex to initiate transcription with Pol II. This allows C. burnetii to control the expression of genes involved in apoptosis, intracellular trafficking, and transcription. IAV interacts with Pol II to alter host transcription. IAV RNA-dependent RNA polymerase (RdRp) interacts with hyperphosphorylated Pol II, causing its degradation. IAV protein PA-X also targets Pol II-specific mRNA transcripts for degradation. L. monocytogenes protein LntA binds BAHD1. This displaces BAHD1 from ISG promoters, resulting in upregulation of ISGs. MeV dampens the host immune response by targeting host transcription factors. One example, depicted here, demonstrates how MeV proteins V and P can target the JAK-STAT pathway by preventing the phosphorylation of STAT1 and STAT2, thus inhibiting their translocation into the nucleus and transcription factor activity. S. flexneri protein OspF dephosphorylates MAPKs inhibiting MAPK-dependent phosphorylation of histone H3, ultimately altering the expression of immune response genes. (C) SARS-CoV-2, HPV, Legionella pneumophila, and Chlamydia trachomatis target histones. Left to right: C.t. protein NUE is a eukaryotic-like SET-domain containing protein with DNA methyltransferase activity. However, the effect on the host transcription landscape is yet to be determined. Viral protein E7 of HPV recruits HDAC1 and JARID1B to the TLR9 promoter region, inhibiting their ability to acetylate and methylate histones. ORF8 of SARS-CoV-2 is a histone mimic, usurping host enzyme KAT2A away from its canonical targets. This results in acetylation of ORF8, degradation of KAT2A, and reduced H3 acetylation. L. pneumophila-secreted effector RomA also contains a eukaryotic-like SET domain with methyltransferase activity. It can methylate histone 3 lysine 14, repressing gene expression. (D) EBV, HIV, IAV, DENV, Coxiella burnetii, Anaplasma phagocytophilum, and Ehrlichia chaffeensis target DNA directly. Left to right: IAV protein NS1 and DENV protein NS5 both bind the PAF1 complex to prevent its interaction with Pol II, inhibiting the transcription of antiviral genes. EBV transcription factors, Zta and Rta, and viral preinitiation complex (vPIC) bind unique sites on the host genome, resulting in “de novo” transcripts that alter the host transcriptional landscape. A. phagocytophilum effector protein AnkA binds AT-rich host DNA where it acts to downregulate the expression of host gene CYBB with the help of recruitment of HDAC1 to deacetylate histone H3. One of the functions of HIV protein Tat is to directly interact with host DNA. Tat interacts with transcription factor ETS1 at promoter sites to alter the expression of ETS1-regulated genes. E. chaffeensis secretes multiple proteins that bind various regions of host DNA including p200 (A-rich Alu-Sx elements), TRP32 (G-rich), TRP47 (G + C rich), and TRP120 (G + C rich), leading to altered transcription. C. burnetii effector CBU1314 binds to the host PAF1 complex, which is important for Pol II regulation. This interaction leads to an altered innate immune response.