Viral Subversion of the Chromosome Region Maintenance 1 Export Pathway and Its Consequences for the Cell Host

Abstract

In eukaryotic cells, the spatial distribution between cytoplasm and nucleus is essential for cell homeostasis. This dynamic distribution is selectively regulated by the nuclear pore complex (NPC), which allows the passive or energy-dependent transport of proteins between these two compartments. Viruses possess many strategies to hijack nucleocytoplasmic shuttling for the benefit of their viral replication. Here, we review how viruses interfere with the karyopherin CRM1 that controls the nuclear export of protein cargoes. We analyze the fact that the viral hijacking of CRM1 provokes are-localization of numerous cellular factors in a suitable place for specific steps of viral replication. While CRM1 emerges as a critical partner for viruses, it also takes part in antiviral and inflammatory response regulation. This review also addresses how CRM1 hijacking affects it and the benefits of CRM1 inhibitors as antiviral treatments.

Keywords: exportin CRM1/XPO-1; nuclear export; nucleocytoplasmic trafficking; viral hijacking; viral infection; virus.

Figure 3

Inhibitors of CRM1. (A) Structure of CRM1 in association with SINE. Domains are coloured as descried in Figure 1. (i) Structure of CRM1 in association with leptomycin B (LMB), in purple. RCSB PDB: 6TVO from [61]. (ii) Structure of CRM1 in association with Selinexor (KPT-330), in purple. RCSB PDB: 7L5E from [62]. The two described SINE inhibit CRM1 nuclear export by interaction with the cysteine 528, located on the NES binding groove. All these figures were generate using PyMOL Molecular Graphics System Version 2.5.5. (B) Table of the CRM1 inhibitors used in antiviral therapy (see Section 5, Discussion) [6,63,64,65,66,67,68].

Figure 1

Structure of CRM1. (A) Schematic representation on CRM1 showing its important motifs. In N-ter, the CRIME motif is colored green. The regulatory heat 9 (H9) is red. The NES pocket (H11 and H12) is blue. Colors are respected in all the different structures. (B) Different experimental crystal structure of CRM1. (i) “Open” structure of CRM1 with low affinity for the cargoes. RCSB PDB: 4FGV from [16]. (ii) Ring structure of CRM1 in association with RanGTP (in cyan), required for active export to cytoplasm. RCSB PDB: 3NC1 from [17]. (iii) Structure of the export complex with high affinity for the cargo, Snuportin (SNUPN—magenta). SNUPN interacts with the NES pocket but additional contacts with CRM1 backbone are required for the stabilization of the complex. To facilitate the visualization, RanGTP has been removed. RCSB PDB: 3GB8 from [18]. (C) Magnification of the SNUPN NES (magenta) orientation in the NES-binding groove of CRM1. Hydrophobic acids (Φ) from the NES sequence are indicated. All the structures were generated using PyMOL Molecular Graphics System Version 2.5.5.

Figure 2

Biological process relying on CRM1. CRM1 exports protein cargoes containing NES. The multiplicity of the biological process dependent on CRM1 were revealed by the study of CRM1 mutants or overexpression in diseases, CRM1 inhibition by synthetic inhibitors and CRM1 interactome. Regulatory proteins include transcription factors that indirectly link CRM1 with several additional cellular functions. These transcriptional effects can also be combined with the RNA export function of CRM1. Overall, CRM1 regulates biological processes through time and space, ensuring the correct localization of proteins for their respective function, but also guarantees the limited residence of active factors in the nucleus to safeguard cellular homeostasis. CRM1 also exerts export-independent functions during snoRNA maturation to target snoRNA to the nucleolus.

Figure 4

Scheme summarizing the consequences of the viral hijacking of CRM1. (1) Upon viral infection, it is well described that CRM1 is hijacked to support vRNA export with a viral NES adaptor or with HuR. (2) The re-localization of cellular proteins is also described as a consequence of CRM1 hijacking, notably to the site of virus assembly or/and virus replication sites. (3) In HAdV, CRM1 plays a crucial role by enhancing the microtubule mediated transport of the virions to the nuclear membrane. (4) In some cases, CRM1 hijacking is involved in the alteration of the NPC composition, affecting the nucleocytoplasmic trafficking.