Advances and transgressions of nuclear transport checkpoint inhibitors

The concept of bidirectional nuclear transport by importins, also known as (aka) karyopherins, and exportins 1 Hawiger J. Zienkiewicz J. Decoding Inflammation, Its Causes, Genomic Responses, and Emerging Countermeasures. Scand. J. Immunol. 2019; 90e12812 Crossref PubMed Scopus (43) Google Scholar ,2 Görlich D. Vogel F. Mills A.D. Hartmann E. Laskey R.A. Distinct functions for the two importin subunits in nuclear protein import. Nature. 1995; 377: 246-248 Crossref PubMed Scopus (413) Google Scholar ,3 Conti E. Kuriyan J. Crystallographic analysis of the specific yet versatile recognition of distinct nuclear localization signals by karyopherin alpha. Structure. 2000; 8: 329-338 Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar ,4 Weis K. Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell. 2003; 112: 441-451 Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar ,5 Wente S.R. Rout M.P. The nuclear pore complex and nuclear transport. Cold Spring Harb. Perspect. Biol. 2010; 2a000562 Crossref PubMed Scopus (525) Google Scholar was followed by the design and development of inhibitors of the nuclear import and export. These inhibitors of nuclear transport checkpoints, targeting importins/karyopherins α and β, have advanced our understanding of the role of proinflammatory, metabolic, and profibrotic signaling to the nucleus in response to multiple causes of inflammation, apoptosis, and fibrosis and their potential therapy. 1 Hawiger J. Zienkiewicz J. Decoding Inflammation, Its Causes, Genomic Responses, and Emerging Countermeasures. Scand. J. Immunol. 2019; 90e12812 Crossref PubMed Scopus (43) Google Scholar ,6 Chiusa M. Hu W. Zienkiewicz J. Chen X. Zhang M.Z. Harris R.C. Vanacore R.M. Bentz J.A. Remuzzi G. Benigni A. et al. EGF receptor-mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling. J. Cell Biol. 2020; 219e202001120 Crossref PubMed Scopus (68) Google Scholar ,7 Chiusa M. Lee Y.A. Zhang M.Z. Harris R.C. Sherrill T. Lindner V. Brooks C.R. Yu G. Fogo A.B. Flynn C.R. et al. Cytoplasmic retention of the DNA/RNA binding protein FUS ameliorates organ fibrosis in mice. J. Clin. Invest. 2024; 134e175158https://doi.org/10.1172/JCI175158 Crossref PubMed Scopus (0) Google Scholar In turn, the inhibitors of nuclear export have helped to unravel the mechanism and treatment of lung and prostate cancer. 8 Quintanal-Villalonga A. Durani V. Sabet A. Redin E. Kawasaki K. Shafer M. Karthaus W.R. Zaidi S. Zhan Y.A. Manoj P. et al. Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers. Sci. Transl. Med. 2023; 15eadf7006 Crossref PubMed Scopus (1) Google Scholar Based on these advances evolving from well-established evidence, we disagree with the content and conclusions of a recent article published in Molecular Therapy by Lee et al. titled “Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation-associated transcription factors.” 9 Lee S. Yoon S.S. Jo M. Kang M. Lee S. Seo Y.J. Park S. Paik Y.K. Jo D. Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation-associated transcription factors. Mol. Ther. 2024; 32: 227-240 Abstract Full Text Full Text PDF PubMed Scopus (0)