Dissecting the import and export pathways of the human RNA helicase UPF1

The RNA helicase UPF1 is best known for its key role in mRNA surveillance but has been implicated in additional cellular processes both in the nucleus and in the cytoplasm. In human cells, the vast majority of UPF1 resides in the cytoplasm and only small amounts can be detected in the nucleus at steady state. It was previously shown that its export from the nucleus to the cytoplasm is Crm1-dependent, yet neither the nuclear export signal (NES) nor the nuclear localization signal (NLS) has been identified. Here, we provide evidence for a noncanonical NLS in UPF1, map the NES to amino acids 89-105 and show that L103 and F105 are essential for UPF1s export to the cytoplasm. Examination of additional UPF1 mutants revealed that a functional helicase domain but not the association with RNA is crucial for the shuttling capacity of UPF1.