Abstract
MAPK signal transduction pathways are important regulators of stress responses, cellular growth, and differentiation. In Neurospora, the circadian clock controls rhythms in phosphorylation of the p38-like MAPK (OS-2); however, the mechanism for this regulation is not known. We show that the WCC, a transcription factor and clock component, binds to the os-4 MAPKKK promoter in response to light and rhythmically in constant darkness, peaking in the subjective morning. Deletion of the WCC binding sites in the os-4 promoter disrupts both os-4 mRNA and OS-2 phosphorylation rhythms. The clock also indirectly regulates rhythmic expression of the histidyl-phosphotransferase gene, hpt-1, which peaks in the evening. Anti-phase expression of positive (OS-4) and negative (HPT-1) MAPK pathway regulators likely coordinate to enhance rhythmic MAPK activation to prepare cells to respond to osmotic stress during the day in the natural environment. Consistent with this idea, we show that wild type cells have a clock-dependent morning kinetic advantage in glycerol accumulation after salt stress as compared to evening treatment. Thus, circadian transcriptional control of MAPK pathway components leads to striking time-of-day-specific effects on the signaling status and physiological response of the pathway.
Highlights
Eukaryotic cells adapt their physiology to respond to changing extracellular conditions for enhanced fitness and survival
We found that the clock- and light-associated white collar complex (WCC) directly regulates the mitogenactivated protein kinase (MAPK) pathway through rhythmic binding to the promoter of the MAPKKK gene os-4, resulting in rhythmic os-4 transcription and osmotic sensing (OS)-4 protein accumulation
The cultures were given an 8-min light pulse prior to Chromatin immuno-precipitation (ChIP) to activate the WCC; we identified the top tier genes involved in light signaling pathways and circadian clock output pathways
Summary
Eukaryotic cells adapt their physiology to respond to changing extracellular conditions for enhanced fitness and survival. When the environment changes on a predictable basis, such as the day/night cycle, an internal timing mechanism called the circadian clock provides the machinery to anticipate the change and program daily rhythms in gene expression to prepare for daily stresses. In this way, the clock provides an adaptive advantage to organisms [3,4]. The mechanistic connection between the clock and the stress responsive MAPK pathway is unknown, and critical to understand how organisms prepare for daily predictable stresses. Defining this link is an important step in understanding how defects in circadian clocks and defects in MAPK pathways cause similar diseases in humans, including immune system dysfunction, heart disease, neurodegenerative disorders, and cancer [6,7,8,9]
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