Governed by surface amino acid composition: HIV capsid passage through the NPC barrier

Nuclear transport receptors (NTRs) carry cargo across the permeability barrier of nuclear pore complexes (NPCs) - an FG phase condensed from disordered but cohesive FG repeats. This phase is repelling to ‘normal’ macromolecules but a good ‘solvent’ for NTRs. HIV delivers its capsid through NPCs into nuclei when infecting non-dividing cells. Those capsids are not transported like cargo but cross the barrier like NTRs. We now uncovered the molecular determinants of this NTR-behavior and found that the FG-binding pocket around CA ^N57 is insufficient. Instead, myriads of transient interactions of exposed capsid sidechains allow the capsid’s outer surface to be ‘wetted’ by FG repeats, making capsids soluble in the phase. We have identified a critical set of such residues whose mutation to ‘FG-repelling’ ones prevents FG phase-partitioning, NPC-targeting, and NPC-passage. We provide direct evidence that CPSF6 releases capsids from NPCs into nuclei, resembling RanGTP in conferring directionality to canonical nuclear import.