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.
Keywords: Period2/SUMO/phosphorylation/ubiquitination/circadian/post-translational modification 26,461 characters without space, excluding references and materials and methods. AbstractCircadian rhythm control by clock proteins, including Period 2 (PER2), is strongly impacted by posttranslational modifications (PTMs) controlling clock protein stability, localization and activity. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had dramatically different effects on PER2 turnover and subcellular localization. PER2-SUMO2 conjugation facilitated PER2 ubiquitination and degradation. In contrast, SUMO1 conjugation mediated by the E3 SUMO-protein ligase RanBP2 led to enhanced CK1-mediated PER2 S662 phosphorylation and also increased PER2 nuclear accumulation, chromatin association and suppression function. PER2 K736 was an important determinant of both SUMO1-and SUMO2-conjugation. A PER2 K736R mutation was sufficient to alter circadian periodicity, reduce PER2 interaction with β-TrCP or CRY1, decrease PER2 nuclear entry and abolish PER2-mediated transcriptional suppression of REV-ERBα, REV-ERBβ and RORγ.Together, our data revealed differential effects of SUMO isoforms on PER2 function and demonstrated the effect of SUMOylation on PER2 coordination of the circadian regulatory system.
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