A Chemokine Targets the Nucleus: Cxcl12-Gamma Isoform Localizes to the Nucleolus in Adult Mouse Heart

Chemokines are extracellular mediators of complex regulatory circuits involved principally in cell-to-cell communication. Most studies to date of the essential chemokine Cxcl12 (Sdf-1) have focused on the ubiquitously expressed secreted isoforms α and β. Here we show that, unlike these isoforms and all other known chemokines, the alternatively transcribed γ isoform is an intracellular protein that localizes to the nucleolus in differentiated mouse Cardiac tissue. Our results demonstrate that nucleolar transportation is encoded by a nucleolar-localization signal in the unique carboxy-terminal region of Sdf-1γ, and is competent both in vivo and in vitro. The molecular mechanism underlying these unusual chemokine properties involves cardiac-specific transcription of an mRNA containing a unique short-leader sequence lacking the signal peptide and translation from a non-canonical CUG codon. Our results provide an example of genome economy even for essential and highly conserved genes such as Cxcl12, and suggest that chemokines can exert tissue specific functions unrelated to cell-to-cell communication.