Circadian Control of Protein Synthesis

Abstract

Daily rhythms in the rate and specificity of protein synthesis occur in most mammalian cells through an interaction between cell-autonomous circadian regulation and daily cycles of systemic cues. However, the overall protein content of a typical cell changes little over 24 h. For most proteins, translation appears to be coordinated with protein degradation, producing phases of proteomic renewal that maximize energy efficiency while broadly maintaining proteostasis across the solar cycle. We propose that a major function of this temporal compartmentalization-and of circadian rhythmicity in general-is to optimize the energy efficiency of protein synthesis and associated processes such as complex assembly. We further propose that much of this temporal compartmentalization is achieved at the level of translational initiation, such that the translational machinery alternates between distinct translational mechanisms, each using a distinct toolkit of phosphoproteins to preferentially recognize and translate different classes of mRNA.

Keywords: biphasic model; circadian rhythms; protein synthesis; temporal compartmentalization; translational initiation.

FIGURE 1

A generalized mechanism of translational initiation, highlighting the major events and core machinery. The cartoon outlines of protein and RNA are based on resolvable regions of published 48S and 80S initiation complexes [84, 242], supplemented with AlphaFold predictions of any missing proteins [243, 244]. Not all initiation mechanisms follow this scheme exactly. In particular, not all mechanisms include the scanning step or use eIF2 to recruit the Met‐tRNA_i ^AUG. The timing of release of the cap‐binding complex might also vary but seems to occur later during translational elongation in at least some circumstances [245].

FIGURE 2

The mTOR signalling pathway, highlighting mTORC1 and interactions that regulate canonical initiation. Green shows procanonical factors, red shows anticanonical factors, and orange shows proteins implicated in the circadian TTFL (which may promote or suppress canonical initiation, depending on context). Solid lines represent direct interactions; dotted lines represent interactions that might be indirect. For regulatory proteins with multiple paralogues, such as AKT1, S6Kβ1, and 4E‐BP1, the related proteins are assumed to function similarly and only one paralogue is shown. Note how multiple branches converge on the cap‐binding complex and the 43S preinitiation complex, which must come together for translational initiation.

FIGURE 3

A speculative structural model of the canonical 48S initiation complex, showing views from the (A) underside and (B) proximal side. This model is based on a recent structure of an intact 48S initiation complex (PDB 6ZMW) [84]. Flexible regions that were not resolvable by electron cryomicroscopy have been modelled using AlphaFold [243, 244] and are shown as translucent. Note that these regions are mobile and mostly predicted to have little or no defined shape; the intention here is to show the complete machinery that must be present in the complex. Almost all the phosphosites (red) are in these flexible regions. Panel C shows additional proteins which stably associated with the canonical 48S initiation complex. Colors are consistent with Figure 1. All structures were taken from AlphaFold, except mTORC1 which is a hybrid model (PDB 6BCX and AlphaFold) [246]. All proteins are shown to scale with the 48S initiation complex.

FIGURE 4

The CK2 signalling pathway, highlighting interactions that regulate canonical initiation. The colour scheme is the same as in Figure 2. Though they are heavily interconnected, we have separated the CK2 and mTOR pathways into separate figures for simplicity.

FIGURE 5

A two‐phase model for cell‐autonomous circadian proteostasis. In the accrual phase, GCN2 suppresses bulk protein synthesis but activates noncanonical mechanisms of translational initiation. This phase of specialized translation modestly alters the composition of the proteome, potentially allowing the cell to survive periods of anticipated nutrient deprivation during the organismal rest phase. In the renewal phase, mTOR and CK2 increase the rate of bulk protein synthesis by selectively activating canonical initiation. At the same time, the rate of bulk protein degradation is increased to maintain the total protein content at a roughly constant level, leading to rapid protein turnover and proteomic renewal.