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Generation of Leukemia‐Associated Nucleoporin Fusion Genes Affects Nuclear Pore Complex Integrity
Author(s) -
Nguyen Nhan,
Saito Shoko,
Kawaguchi Atsushi,
Okuwaki Mitsuru
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04966
Subject(s) - nucleoporin , nuclear pore , fusion protein , microbiology and biotechnology , cytoplasm , biology , fusion gene , chromosomal translocation , gene knockdown , gene , nuclear transport , cell nucleus , genetics , recombinant dna
Trafficking of macromolecules between the nucleus and the cytoplasm occurs selectively through the nuclear pore complexes (NPCs). NPCs are comprised of approximately 30 nucleoporins (Nups), among which N UP98 and NUP214 genes are fused to partner genes in hematopoietic malignancies. Chromosome translocations of the NUP98 and NUP214 genes lead to two outcomes. One involves the appearance of mutant proteins containing parts of Nup98 or Nup214; the other involves a reduction of full‐length Nup98 or Nup214 in cells. It is currently poorly understood the mechanisms how fusion genes induce leukemia, and the effects of Nup fusion proteins appearance and decreased full‐length Nups on NPC functions. Therefore, we aimed to clarify the effects of the expression of Nup fusion proteins and reduction of Nups on the localizations of other Nups. We found that Nup62, Nup88, and Nup98 were mislocalized upon the expression of Nup214‐fusion proteins, whereas Nup62 was mislocalized upon the expression of Nup98‐fusion proteins. The fusion proteins interacted with endogenous Nups via Nup214 and Nup98 portions of Nup214‐ and Nup98‐fusion proteins, respectively. Nup98 was required for the stabilization of Nup214‐fusion proteins. Moreover, NUP98 knockdown caused a decreased expression of most Nups tested, whereas NUP214 knockdown decreased Nup88, which is a component in the cytoplasmic subcomplex of NPCs. Taken together, our results suggest that chromosome translocations involving NUP98 and NUP214 impair the integrity of NPCs by inducing mislocalization and decreased expression of NPC components.