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KPNB1 mediates PER/CRY nuclear translocation and circadian clock function.

Lee Y, Jang AR, Francey LJ, Sehgal A, Hogenesch JB - Elife (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed model for KPNB1 function in nuclear translocation of PERs/CRYs controlling negative feedback regulation of the molecular clock.KPNB1 directly associates with PERs/CRYs and guides their nuclear entry thus facilitating negative feedback repression of CLOCK/BMAL1-mediated transcription of the repressor genes.DOI:http://dx.doi.org/10.7554/eLife.08647.017
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fig6: Proposed model for KPNB1 function in nuclear translocation of PERs/CRYs controlling negative feedback regulation of the molecular clock.KPNB1 directly associates with PERs/CRYs and guides their nuclear entry thus facilitating negative feedback repression of CLOCK/BMAL1-mediated transcription of the repressor genes.DOI:http://dx.doi.org/10.7554/eLife.08647.017

Mentions: Timely nuclear translocation of the PER/CRY (or Per/Tim) repressor complex is a critical and conserved step in maintaining rhythmicity in metazoans. However, the functional carrier molecules responsible for nuclear localization of the feedback regulators have yet to be determined. Our study provides the first evidence that KPNB1 plays a key role as a nuclear transporter of the PER/CRY complex in negative feedback repression in both mammalian and fly clocks (Figure 6).10.7554/eLife.08647.017Figure 6.Proposed model for KPNB1 function in nuclear translocation of PERs/CRYs controlling negative feedback regulation of the molecular clock.


KPNB1 mediates PER/CRY nuclear translocation and circadian clock function.

Lee Y, Jang AR, Francey LJ, Sehgal A, Hogenesch JB - Elife (2015)

Proposed model for KPNB1 function in nuclear translocation of PERs/CRYs controlling negative feedback regulation of the molecular clock.KPNB1 directly associates with PERs/CRYs and guides their nuclear entry thus facilitating negative feedback repression of CLOCK/BMAL1-mediated transcription of the repressor genes.DOI:http://dx.doi.org/10.7554/eLife.08647.017
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4597257&req=5

fig6: Proposed model for KPNB1 function in nuclear translocation of PERs/CRYs controlling negative feedback regulation of the molecular clock.KPNB1 directly associates with PERs/CRYs and guides their nuclear entry thus facilitating negative feedback repression of CLOCK/BMAL1-mediated transcription of the repressor genes.DOI:http://dx.doi.org/10.7554/eLife.08647.017
Mentions: Timely nuclear translocation of the PER/CRY (or Per/Tim) repressor complex is a critical and conserved step in maintaining rhythmicity in metazoans. However, the functional carrier molecules responsible for nuclear localization of the feedback regulators have yet to be determined. Our study provides the first evidence that KPNB1 plays a key role as a nuclear transporter of the PER/CRY complex in negative feedback repression in both mammalian and fly clocks (Figure 6).10.7554/eLife.08647.017Figure 6.Proposed model for KPNB1 function in nuclear translocation of PERs/CRYs controlling negative feedback regulation of the molecular clock.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus