Fig. 3.

Schematic representation of the mechanisms of regulation of IMP/EXP-dependent nuclear transport, as illustrated by examples of viral proteins. In intramolecular masking (1) IMPs/EXPs are prevented from binding the NLS/NES of the cargo by masking of the NLS/NES by sequences within the same protein. This is exemplified by (a) the human T-cell leukaemia virus type 2 (HTLV-2) Rex protein in its inactive p24 form, where specific phosphorylation by CK1/GSK3 at T¹⁶⁴ and subsequent phosphorylation at S^151/153 are required for IMPβ recognition of the NLS, and (b) the VZV IE62, where phosphorylation at S⁶⁸⁶ by the VZV kinase ORF66 inhibits nuclear import by impairing recognition by IMPα/β1 [97]. Examples of intramolecular masking in nuclear export are shown for (c) HPV E1, where Cdk mediated phosphorylation of S¹⁰⁷ prevents Crm1 binding, resulting in nuclear retention [24], [84], and (d) CAV VP3, where phosphorylation of T¹⁰⁸ specifically in cancer cells prevents nuclear export [114], [115]. In intermolecular masking (2), NLSs/NESs are masked from IMPs/EXPs binding by a heterologous protein/molecule. An example in the case of nuclear import is the cytoplasmic protein BRAP2 which, dependent on Cdk phosphorylation of T¹²⁴, prevents recognition by IMPα/β1 of the SV40 T-ag NLS, a similar mechanism dependent on protein kinase C phosphorylation of T⁴²⁷ applies to HCMV ppUL44 protein (not shown) [78]. Enhanced nuclear import/export can occur through posttranslational modification enhancing NLS/NES recognition by IMP/EXP. An example (3a) is the increase in the affinity of binding of IMPα/β1 to the NLSs of HCMV ppUL44 and SV40 T-ag (not shown) by CK2 phosphorylation (of S⁴¹³ and S^111/112 respectively) leading to enhanced nuclear import [23], [85], [87]. In the case of nuclear export (3b), Cdk1/Cdk2 mediated phosphorylation of S⁸⁹ enhances recognition of the Adenovirus type 5 E1a NES by Crm1, leading to more efficient nuclear export [111].