Abstract
Posttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2 interaction with β-TrCP leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation, inhibited PER2 degradation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter PER2 protein oscillation and reduce PER2-mediated transcriptional suppression. Together, our data revealed that SUMO1 versus SUMO2 conjugation acts as a determinant of PER2 stability and function and thereby affects the circadian regulatory system and the expression of clock-controlled genes.
Highlights
The circadian clock controls many rhythmic physiological processes such as hormonal oscillation, metabolism and immune function that are essential to maintain h omeostasis[1,2]
The core clock proteins are known to be regulated by several types of Posttranslational modification (PTM), it is likely that additional layers of clock-related PTM regulation remain to be discovered
Consistent with previous findings that S662 phosphorylation mainly promotes PER2 protein nuclear retention and stabilization[15], our data suggested that RanBP2-mediated PER2-SUMO1 conjugation enhances casein kinase 1 (CK1)-mediated PER2 phosphorylation at S662 (Fig. 4) and promotes PER2 transcriptional suppression function (Fig. 3)
Summary
The circadian clock controls many rhythmic physiological processes such as hormonal oscillation, metabolism and immune function that are essential to maintain h omeostasis[1,2]. PER2 suppresses BMAL/CLOCK mediated transcription by displacing BMAL/CLOCK/CRY complexes from their target promoters This displacement is important for inhibition of circadian gene expression, and essential for reactivation of the T TFL5. This switch and determine which site CK1 will phosphorylate remain unknown This illustrates how, even for a relatively well studied protein like PER2, interaction and cross regulation between PTMs that control protein function can be complex and not well understood. Whether other PTMs are part of this interactive regulation of PER2 that influences the speed of circadian clock[25] remains unknown Despite these many lines of evidence showing the important of PER2 PTMs, little is known about PER2 SUMOylation. SUMOylation can alter protein–protein interactions, subcellular localization or protein activity and can participate in transcriptional r egulation[26,27]. Whether or not other transcriptional regulators are affected by SUMO1 versus SUMO2/3 conjugation is unknown
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