Nuclear import of BCL11B is mediated by a classical nuclear localization signal and not the Krüppel-like zinc fingers.

The Krüppel-like transcription factor BCL11B is characterized by wide tissue distribution and crucial functions in key developmental and cellular processes and various pathologies including cancer or HIV infection. Although basics of BCL11B activity and relevant interactions with other proteins were uncovered, how this exclusively nuclear protein localizes to its compartment remained unclear. Here, we demonstrate that unlike other KLFs, BCL11B does not require the C-terminal DNA-binding domain to pass through the nuclear envelope but encodes an independent, previously unidentified nuclear localization signal (NLS) which is located distantly from the zinc finger domains and fulfills the essential criteria of an autonomous NLS. First, it can redirect a heterologous cytoplasmic protein to the nucleus. Second, its mutations cause aberrant localization of the protein of origin. Finally, we provide experimental and in silico evidences of the direct interaction with importin alpha. The relative conservation of this motif allows formulating a consensus sequence (K/R)K-X13-14-KR+K++ which can be found in all BCL11B orthologues among vertebrates and in the closely related protein BCL11A.