Identification of a signal for rapid export of proteins from the nucleus

TLDR

Nuclear export mechanisms are poorly understood, yet trafficking of the catalytic subunit of cAMP‑dependent protein kinase is essential for gene regulation. The heat‑stable inhibitor of cAMP‑dependent protein kinase contains a 15‑residue nuclear export signal (residues 35–49) that, when fused to heterologous proteins, drives rapid nuclear export; hydrophobic residues are essential, and the minimal core LALKLAGLDI (residues 37–46) is sufficient, illustrating a protein‑based NES distinct from RNA‑associated signals.

Abstract

Active nuclear import of protein is controlled by nuclear localization signals (NLSs), but nuclear export is not understood well. Nuclear trafficking of the catalytic (C) subunit of cAMP-dependent protein kinase (cAPK) is critical for regulation of gene expression. The heat-stable inhibitor (PKl) of cAPK contains a nuclear export signal (NES) that triggers rapid, active net extrusion of the C-PKl complex from the nucleus. This NES (residues 35-49), fused or conjugated to heterologous proteins, was sufficient for rapid nuclear export. Hydrophobic residues were critical. The NES is a slightly weaker signal than the SV40 NLS. A sequence containing only residues 37-46, LALKLAGLDI, is also sufficient for nuclear export. This is an example of a protein-based NES having no obvious association with RNA. A similar sequence, LQLPPLERLTL, from Rev, an RNA-binding protein of HIV-1, also is an NES.