KPNB1 mediates PER/CRY nuclear translocation and circadian clock function

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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 NFAT (NRON) ribonucleoprotein (RNP) complex, mediates nuclear translocation and repressor function of the PER/CRY complex. RNAi depletion of KPNB1 trapped the PER/CRY complex in cytoplasm by blocking nuclear entry of PER proteins in human cells. KPNB1 interacted mainly with PER proteins and directed PER/CRY nuclear transport in circadian fashion. Interestingly, KPNB1 regulated 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 abolished 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 circadian clock.

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Yool Lee

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

Competing interests
The authors declare that no competing interests exist.
A Reum Jang

Department of Neuroscience, Howard Hughes Medical Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Lauren J Francey

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

Competing interests
The authors declare that no competing interests exist.
Amita Sehgal

Department of Neuroscience, Howard Hughes Medical Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
John B Hogenesch

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

For correspondence
hogenesc@mail.med.upenn.edu

Competing interests
The authors declare that no competing interests exist.

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