title: Nuclear translocation of the N-terminal prodomain of interleukin-16.
abstract: Interleukin-16 (IL-16) is a pleiotropic cytokine that functions as a chemoattractant factor, a modulator of T cell activation, and an inhibitor of human immunodeficiency virus (HIV) replication. These diverse functions are exclusively attributed to the secreted C-terminal peptide of 121 amino acids (mature IL-16), which is cleaved from the precursor protein (pro-IL-16) by caspase-3. Human pro-IL-16 is comprised of 631 amino acids with three PDZ domains, one of which is present in secreted mature IL-16. No cellular localization or biologic functions have been ascribed to the unusually large and highly conserved N-terminal prodomain formed as a result of proteolytic release of the third PDZ domain of pro-IL-16. Here we show that the N-terminal prodomain of pro-IL-16 translocates into the nucleus following cleavage of the C-terminal segment. The nuclear localization signal of pro-IL-16 consists of a classical bipartite nuclear targeting motif. We also show that the nuclear targeting of the IL-16 prodomain induces a G(0)/G(1) arrest in the cell cycle. Taken together, the high degree of conservation of the prodomain among species, the presence of two PDZ motifs, and the nuclear localization and subsequent inhibitory effect on cell cycle progression suggest that pro-IL-16 is cleaved into two functional proteins, a C-terminal-secreted cytokine and an N-terminal product, which affects the cell cycle.
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA. yzhang@bupula.bu.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Kornfeld
authors.forename: W W
authors.initials: WW
authors.lastname: Cruikshank
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: C C
authors.initials: CC
authors.lastname: Reardon
authors.forename: D M
authors.initials: DM
authors.lastname: Center
mesh_terms: D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D049452:Green Fluorescent Proteins; D006801:Humans; D019410:Interleukin-16 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D019410:Interleukin-16; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins