Author ORCID Identifier
Date of Graduation
Masters of Science (MS)
Mark J. Burish
Protein turnover is one of the most essential mechanisms controlling circadian rhythms. F-Box and Leucine Rich Repeat Protein21 (FBXL21) is a circadian E3 ligase which shows oscillatory mRNA transcripts and protein levels. It was previously found to perform subcellular compartment-specific E3 ligase activities targeting the core clock proteins CRYPTOCHROME(CRY)1/2. Here we identified a new sarcomeric target substrate, Telethonin(TCAP), which also shows circadian oscillation in its mRNA transcript and protein expression and, importantly, interaction with FBXL21 in an anti-phasic manner. Via computational and pharmacological tests, we identified Glycogen Synthase Kinase-3β(GSK-3β) as a regulator of FBXL21. Biochemical and molecular characterizations demonstrated that GSK-3β interacts with both FBXL21 and TCAP and affects Skp, Cullin1(Cul1), F-box containing (SCF) complex/E3 ligase-Substrate complex formation. Interestingly, GSK-3β knockdown significantly inhibited FBXL21-CUL11 and FBXL21-TCAP complex formation. These results revealed a new circadian regulatory pathway that FBXL21 regulates TCAP via ubiquitin-mediated proteasomal pathway in the cytoplasm coordinatively with GSK-3β.
FBXL21, TCAP, Telethonin, GSK-3β, E3 ligase, SCF complex, Circadian, Ubiquitin, Proteasomal pathway