Death of a Protein: The Role of E3 Ubiquitin Ligases in Circadian Rhythms of Mice and Flies

Abstract

Circadian clocks evolved to enable organisms to anticipate and prepare for periodic environmental changes driven by the day–night cycle. This internal timekeeping mechanism is built on autoregulatory transcription–translation feedback loops that control the rhythmic expression of core clock genes and their protein products. The levels of clock proteins rise and ebb throughout a 24-h period through their rhythmic synthesis and destruction. In the ubiquitin–proteasome system, the process of polyubiquitination, or the covalent attachment of a ubiquitin chain, marks a protein for degradation by the 26S proteasome. The process is regulated by E3 ubiquitin ligases, which recognize specific substrates for ubiquitination. In this review, we summarize the roles that known E3 ubiquitin ligases play in the circadian clocks of two popular model organisms: mice and fruit flies. We also discuss emerging evidence that implicates the N-degron pathway, an alternative proteolytic system, in the regulation of circadian rhythms. We conclude the review with our perspectives on the potential for the proteolytic and non-proteolytic functions of E3 ubiquitin ligases within the circadian clock system.

Lysine-independent ubiquitination and degradation of REV-ERBα involves a bi-functional degradation control sequence at its N-terminus

“…This includes lysine-independent ubiquitination and degradation, which implies perhaps Nterminal ubiquitination. The properties of these regulatory elements fit into a general theme of how degradation is controlled for many different proteins (48)(49)(50)(51), but they appear to be all packaged into the first 25AAs at the N-terminus for REV-ERB. The degradation blocking activity of AA2-9 appears to be non-sequence specific but length dependent, explainable by the composition of these amino acids that are predicted to be an intrinsic disordered region.…”

“…Overall, we have discovered several important components that regulate the degradation of REV-ERB. The properties of these regulatory elements fit into a general theme of how degradation is controlled for many proteins (46)(47)(48). Recently, Cryo-EM was able to resolve the detailed interactions (49-51) of various components with the proteasome throughout the degradation process.…”

E3-ubiquitin ligases and recent progress in osteoimmunology

“…Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. E1 activates ubiquitin and forms an E1-ubiquitin intermediate, and ubiquitin is transferred from E1 to E2, leading to the formation of an E2-ubiquitin intermediate (1)(2)(3). Then E3 recognizes its substrate proteins and the E2-ubiquitin intermediate, resulting in the formation of a protein complex and transference of the activated ubiquitin from E2 to most often a lysine residue in the substrates (4).…”

“…Then E3 recognizes its substrate proteins and the E2-ubiquitin intermediate, resulting in the formation of a protein complex and transference of the activated ubiquitin from E2 to most often a lysine residue in the substrates (4). Ubiquitin has seven lysine residues, including K6, K11, K27, K29, K33, K48 and K63, that are used as attachment sites for subsequent Ub proteins (1,2,4), while K48-linked chains are the most abundant linkages for polyubiquitylation. This process is repeated to form a polyubiquitin chain, and ubiquitintagged proteins are recognized and degraded into small fragments by the 26S proteasome.…”