Pathogenic Neisseria species, the causative agents of gonorrhoea and bacterial meningitis, encode a family of polymorphic exo-proteins which are autoproteolytically processed into several distinct extracellular components, including an IgA1 protease and an α-protein. IgA1 protease, a putative virulence determinant, is a sequence-specific endopeptidase known to cleave human IgA1, but additional target proteins have been postulated. The physical linkage of IgA1 protease and a-protein suggests a functional relationship of both precursor components. Previous work has shown that α-protein is essential neither for extracellular transport nor for the proteolytic activity of IgA1 protease. Intriguingly, α-proteins carry amino acid sequences reminiscent of nuclear location signals of viral and eukaryotic proteins. Here we demonstrate the functionality of these nuclear location signal sequences in transfected eukaryotic cells. Chimeric α-proteins show nuclear transport and selectively associate with nucleolar structures. More importantly, native purified α-proteins are capable of entering certain human primary cells from the exterior via an endocytotic route and accumulate in the nuclei. The neisserial α-proteins share several features with eukaryotic transcription factors, such as the formation of dimers via a heptad repeat sequence. We propose a role for a-proteins in the regulation of host-cell functions. As the α-proteins are covalently connected with IgA1 protease they may also serve as carriers for the IgA1 protease into human cells where additional proteolytic targets may exist. Neisseria meningitidis, which locally colonizes the nasopharyngeal mucosa of many human individuals without apparently causing symptoms, secretes this nucleus-targeted factor in large quantities.