The MAP kinase p38 is part of Drosophila melanogaster's circadian clock

Verena Dusik, Pingkalai R. Senthilan, Benjamin Mentzel, Heiko Hartlieb, Corinna Wülbeck, Taishi Yoshii, Thomas Raabe, Charlotte Helfrich-Förster

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ∼ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential "clock kinase" phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways.

Original languageEnglish
Pages (from-to)e1004565
JournalPLoS Genetics
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 1 2014

Fingerprint

Circadian Clocks
p38 Mitogen-Activated Protein Kinases
Drosophila melanogaster
mitogen-activated protein kinase
circadian rhythm
neurons
Darkness
Neurons
Light
Drosophila
phosphotransferases (kinases)
Western blotting
Phosphotransferases
Western Blotting
Period Circadian Proteins
protein
organisms
Protein Transport
Locomotion
Diptera

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dusik, V., Senthilan, P. R., Mentzel, B., Hartlieb, H., Wülbeck, C., Yoshii, T., ... Helfrich-Förster, C. (2014). The MAP kinase p38 is part of Drosophila melanogaster's circadian clock. PLoS Genetics, 10(8), e1004565. https://doi.org/10.1371/journal.pgen.1004565

The MAP kinase p38 is part of Drosophila melanogaster's circadian clock. / Dusik, Verena; Senthilan, Pingkalai R.; Mentzel, Benjamin; Hartlieb, Heiko; Wülbeck, Corinna; Yoshii, Taishi; Raabe, Thomas; Helfrich-Förster, Charlotte.

In: PLoS Genetics, Vol. 10, No. 8, 01.08.2014, p. e1004565.

Research output: Contribution to journalArticle

Dusik, V, Senthilan, PR, Mentzel, B, Hartlieb, H, Wülbeck, C, Yoshii, T, Raabe, T & Helfrich-Förster, C 2014, 'The MAP kinase p38 is part of Drosophila melanogaster's circadian clock', PLoS Genetics, vol. 10, no. 8, pp. e1004565. https://doi.org/10.1371/journal.pgen.1004565
Dusik V, Senthilan PR, Mentzel B, Hartlieb H, Wülbeck C, Yoshii T et al. The MAP kinase p38 is part of Drosophila melanogaster's circadian clock. PLoS Genetics. 2014 Aug 1;10(8):e1004565. https://doi.org/10.1371/journal.pgen.1004565
Dusik, Verena ; Senthilan, Pingkalai R. ; Mentzel, Benjamin ; Hartlieb, Heiko ; Wülbeck, Corinna ; Yoshii, Taishi ; Raabe, Thomas ; Helfrich-Förster, Charlotte. / The MAP kinase p38 is part of Drosophila melanogaster's circadian clock. In: PLoS Genetics. 2014 ; Vol. 10, No. 8. pp. e1004565.
@article{dab3d17f1bd34666935f1826ca033724,
title = "The MAP kinase p38 is part of Drosophila melanogaster's circadian clock",
abstract = "All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ∼ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential {"}clock kinase{"} phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways.",
author = "Verena Dusik and Senthilan, {Pingkalai R.} and Benjamin Mentzel and Heiko Hartlieb and Corinna W{\"u}lbeck and Taishi Yoshii and Thomas Raabe and Charlotte Helfrich-F{\"o}rster",
year = "2014",
month = "8",
day = "1",
doi = "10.1371/journal.pgen.1004565",
language = "English",
volume = "10",
pages = "e1004565",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - The MAP kinase p38 is part of Drosophila melanogaster's circadian clock

AU - Dusik, Verena

AU - Senthilan, Pingkalai R.

AU - Mentzel, Benjamin

AU - Hartlieb, Heiko

AU - Wülbeck, Corinna

AU - Yoshii, Taishi

AU - Raabe, Thomas

AU - Helfrich-Förster, Charlotte

PY - 2014/8/1

Y1 - 2014/8/1

N2 - All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ∼ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential "clock kinase" phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways.

AB - All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ∼ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential "clock kinase" phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways.

UR - http://www.scopus.com/inward/record.url?scp=84917699831&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84917699831&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1004565

DO - 10.1371/journal.pgen.1004565

M3 - Article

C2 - 25144774

AN - SCOPUS:84917699831

VL - 10

SP - e1004565

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 8

ER -