Tumor suppressor BAP1 nuclear import is governed by transportin-1

J Cell Biol. 2022 Jun 6;221(6):e202201094. doi: 10.1083/jcb.202201094. Epub 2022 Apr 21.


Subcellular localization of the deubiquitinating enzyme BAP1 is deterministic for its tumor suppressor activity. While the monoubiquitination of BAP1 by an atypical E2/E3-conjugated enzyme UBE2O and BAP1 auto-deubiquitination are known to regulate its nuclear localization, the molecular mechanism by which BAP1 is imported into the nucleus has remained elusive. Here, we demonstrated that transportin-1 (TNPO1, also known as Karyopherin β2 or Kapβ2) targets an atypical C-terminal proline-tyrosine nuclear localization signal (PY-NLS) motif of BAP1 and serves as the primary nuclear transporter of BAP1 to achieve its nuclear import. TNPO1 binding dissociates dimeric BAP1 and sequesters the monoubiquitination sites flanking the PY-NLS of BAP1 to counteract the function of UBE2O that retains BAP1 in the cytosol. Our findings shed light on how TNPO1 regulates the nuclear import, self-association, and monoubiquitination of BAP1 pertinent to oncogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus*
  • Cell Nucleus / metabolism
  • Humans
  • Nuclear Localization Signals* / metabolism
  • Proline / metabolism
  • Tumor Suppressor Proteins*
  • Tyrosine / metabolism
  • Ubiquitin Thiolesterase*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • beta Karyopherins* / metabolism


  • BAP1 protein, human
  • Nuclear Localization Signals
  • TNPO1 protein, human
  • Tumor Suppressor Proteins
  • beta Karyopherins
  • Tyrosine
  • Proline
  • Ubiquitin-Conjugating Enzymes
  • UBE2O protein, human
  • Ubiquitin Thiolesterase