Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism

Abstract

Intermediary metabolism studies have typically concentrated on four major regulatory mechanisms—substrate availability, allosteric enzyme regulation, post-translational enzyme modification, and regulated enzyme synthesis. Although transcriptional control has been a big focus, it is becoming increasingly evident that many post-transcriptional events are deeply embedded within the core regulatory circuits of enzyme synthesis/breakdown that maintain metabolic homeostasis. The prominent post-transcriptional mechanisms affecting intermediary metabolism include alternative pre-mRNA processing, mRNA stability and translation control, and the more recently discovered regulation by noncoding RNAs. In this review, we discuss the latest advances in our understanding of these diverse mechanisms at the cell-, tissue- and organismal-level. We also highlight the dynamics, complexity and non-linear nature of their regulatory roles in metabolic decision making, and deliberate some of the outstanding questions and challenges in this rapidly expanding field.

daf-16/FoxO promotes gluconeogenesis and trehalose synthesis during starvation to support survival

“…Intermediary metabolism is subject to extensive post-translational regulation ( Arif et al, 2017 ), and such regulation likely reinforces the patterns of transcriptional regulation we describe for L1 starvation. Although the changes in mRNA abundance we report are statistically significant with concerted effects on carbon metabolism, in many cases the fold-changes are relatively modest.…”

The RNA-Binding Protein YBX3 Controls Amino Acid Levels by Regulating SLC mRNA Abundance

“…SLC protein complexes, such as the L1 system, form the core of specialized transporters that facilitate the exchange of amino acids across membranes (Fotiadis et al, 2013;Hediger et al, 2013;Verrey et al, 2004). As SLCs control the pool of LNAA, their expression is coordinated by a number of processes ranging from transcription to protein stability (Arif et al, 2017; Brö er and Brö er, 2017; Fotiadis et al, 2013;Hediger et al, 2013;Lin et al, 2015;Verrey et al, 2004 LNAA transport through combined transcriptional and post-transcriptional control of the SLCs SLC7A5 and SLC3A2. Depletion of YBX3 reduces the transcript levels of SLC7A5 and SLC3A2 ( Figure 3A) by decreasing transcription ( Figure 3D) and destabilizing the mRNAs (Figure 3C), which reduces SLC7A5 and SLC3A2 protein levels ( Figure 3A) and ultimately attenuates steady-state levels of LNAAs ( Figure 4B).…”

Alternative Splicing in Hepatocellular Carcinoma

“… 19 , 20 Alternative splicing and other post-transcriptional control mechanisms, such as mRNA turnover and translation, are integrated with gene transcription to regulate key aspects of cellular metabolism. 21 A prime example of this is the regulation of insulin signaling by a controlled rate of insulin mRNA translation, 22 glucose-mediated insulin mRNA stabilization, 23 and alternative splicing of the insulin receptor. 24 Insulin, in turn, controls the expression of more than 1000 liver transcripts, including both coding and noncoding RNAs.…”