Nuclear Translocation of the N-terminal prodomain of interleukin-16

Interleukin-18 (IL-16) is a pleiotropic cytokine that functions as a chemoa ttractant factor, a modulator of T cell activation, and an inhibitor of hum an immunodeficiency virus (HIV) replication. These diverse functions are ex clusively 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 d omains, one of which is present in secreted mature IL-16, No cellular local ization or biologic functions have been ascribed to the unusually large and highly conserved N-terminal prodomain formed as a result of proteolytic re lease of the third PDZ domain of pro-IL-16, Here we show that the N-termina l prodomain of pro-IL-16 translocates into the nucleus following cleavage o f the C-terminal segment. The nuclear localization signal of pro-IL-16 cons ists of a classical bipartite nuclear targeting motif, We also show that th e nuclear targeting of the IL-16 prodomain induces a G(0)/G(1) arrest in th e cell cycle. Taken together, the high degree of conservation of the prodom ain among species, the presence of two PDZ motifs, and the nuclear localiza tion and subsequent inhibitory effect on cell cycle progression suggest tha t pro-IL-16 is cleaved into two functional proteins, a C-terminal-secreted cytokine and an N-terminal product, which affects the cell. cycle.