title: KPNB1 mediates PER/CRY nuclear translocation and circadian clock function.
abstract: Regulated nuclear translocation of the PER/CRY repressor complex is critical for negative feedback regulation of the circadian clock of mammals. However, the precise molecular mechanism is not fully understood. Here, we report that KPNB1, an importin β component of the ncRNA repressor of nuclear factor of activated T cells (NRON) ribonucleoprotein complex, mediates nuclear translocation and repressor function of the PER/CRY complex. RNAi depletion of KPNB1 traps the PER/CRY complex in the cytoplasm by blocking nuclear entry of PER proteins in human cells. KPNB1 interacts mainly with PER proteins and directs PER/CRY nuclear transport in a circadian fashion. Interestingly, KPNB1 regulates the PER/CRY nuclear entry and repressor function, independently of importin α, its classical partner. Moreover, inducible inhibition of the conserved Drosophila importin β in lateral neurons abolishes behavioral rhythms in flies. Collectively, these data show that KPNB1 is required for timely nuclear import of PER/CRY in the negative feedback regulation of the circadian clock.
authors: Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
authors: Yool
authors: http://orcid.org/0000-0003-0498-3342
authors: Y
authors: Lee
authors: Department of Neuroscience, Howard Hughes Medical Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.
authors: A Reum
authors: http://orcid.org/0000-0001-8347-7848
authors: AR
authors: Jang
authors: Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
authors: Lauren J
authors: http://orcid.org/0000-0002-9700-2277
authors: LJ
authors: Francey
authors: Department of Neuroscience, Howard Hughes Medical Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.
authors: Amita
authors: http://orcid.org/0000-0001-7354-9641
authors: A
authors: Sehgal
authors: Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
authors: John B
authors: http://orcid.org/0000-0002-9138-8973
authors: JB
authors: Hogenesch
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D057906:Circadian Clocks; D056931:Cryptochromes / Q000378:metabolism*; D004330:Drosophila; D025461:Feedback, Physiological; D006801:Humans; D056950:Period Circadian Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: C538963:CRY1 protein, human; D056931:Cryptochromes; C424166:KPNB1 protein, human; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D012097:Repressor Proteins; D028961:beta Karyopherins
keywords: CRY; D. melanogaster; KPNB1; PER; cell biology; circadian clock; evolutionary biology; genomics; human; mouse; nuclear entry