Protein-Metabolite Interactions Shape Cellular Metabolism and Physiology.

Protein-metabolite interactions regulate many important cellular processes but still remain understudied. Recent technological advancements are gradually uncovering the complexity of the protein-metabolite interactome. Here, we highlight some classic and recent examples of how protein metabolite interactions regulate metabolism, both locally and globally, and how this contributes to cellular physiology. We also discuss the importance of these interactions in diseases such as cancer.

When yeast cells change their mind: cell cycle "Start" is reversible under starvation.

Eukaryotic cells decide in late G1 phase of the cell cycle whether to commit to another round of division. This point of cell cycle commitment is termed "Restriction Point" in mammals and "Start" in the budding yeast Saccharomyces cerevisiae. At Start, yeast cells integrate multiple signals such as pheromones and nutrients, and will not pass Start if nutrients are lacking. However, how cells respond to nutrient depletion after the Start decision remains poorly understood. Here, we analyze how post-Start cells respond to nutrient depletion, by monitoring Whi5, the cell cycle inhibitor whose export from the nucleus determines Start. Surprisingly, we find that cells that have passed Start can re-import Whi5 into the nucleus. In these cells, the positive feedback loop activating G1/S transcription is interrupted, and the Whi5 repressor re-binds DNA. Cells which re-import Whi5 become again sensitive to mating pheromone, like pre-Start cells, and CDK activation can occur a second time upon replenishment of nutrients. These results demonstrate that upon starvation, the commitment decision at Start can be reversed. We therefore propose that cell cycle commitment in yeast is a multi-step process, similar to what has been suggested for mammalian cells.

Perturbations in plant energy homeostasis prime lateral root initiation via SnRK1-bZIP63-ARF19 signaling.

Plants adjust their energy metabolism to continuous environmental fluctuations, resulting in a tremendous plasticity in their architecture. The regulatory circuits involved, however, remain largely unresolved. In Arabidopsis, moderate perturbations in photosynthetic activity, administered by short-term low light exposure or unexpected darkness, lead to increased lateral root (LR) initiation. Consistent with expression of low-energy markers, these treatments alter energy homeostasis and reduce sugar availability in roots. Here, we demonstrate that the LR response requires the metabolic stress sensor kinase Snf1-RELATED-KINASE1 (SnRK1), which phosphorylates the transcription factor BASIC LEUCINE ZIPPER63 (bZIP63) that directly binds and activates the promoter of AUXIN RESPONSE FACTOR19 (ARF19), a key regulator of LR initiation. Consistently, starvation-induced ARF19 transcription is impaired in bzip63 mutants. This study highlights a positive developmental function of SnRK1. During energy limitation, LRs are initiated and primed for outgrowth upon recovery. Hence, this study provides mechanistic insights into how energy shapes the agronomically important root system.

The Arabidopsis bZIP11 transcription factor links low-energy signalling to auxin-mediated control of primary root growth.

Plants have to tightly control their energy homeostasis to ensure survival and fitness under constantly changing environmental conditions. Thus, it is stringently required that energy-consuming stress-adaptation and growth-related processes are dynamically tuned according to the prevailing energy availability. The evolutionary conserved SUCROSE NON-FERMENTING1 RELATED KINASES1 (SnRK1) and the downstream group C/S1 basic leucine zipper (bZIP) transcription factors (TFs) are well-characterised central players in plants' low-energy management. Nevertheless, mechanistic insights into plant growth control under energy deprived conditions remains largely elusive. In this work, we disclose the novel function of the low-energy activated group S1 bZIP11-related TFs as regulators of auxin-mediated primary root growth. Whereas transgenic gain-of-function approaches of these bZIPs interfere with the activity of the root apical meristem and result in root growth repression, root growth of loss-of-function plants show a pronounced insensitivity to low-energy conditions. Based on ensuing molecular and biochemical analyses, we propose a mechanistic model, in which bZIP11-related TFs gain control over the root meristem by directly activating IAA3/SHY2 transcription. IAA3/SHY2 is a pivotal negative regulator of root growth, which has been demonstrated to efficiently repress transcription of major auxin transport facilitators of the PIN-FORMED (PIN) gene family, thereby restricting polar auxin transport to the root tip and in consequence auxin-driven primary root growth. Taken together, our results disclose the central low-energy activated SnRK1-C/S1-bZIP signalling module as gateway to integrate information on the plant's energy status into root meristem control, thereby balancing plant growth and cellular energy resources.

A Candida albicans regulator of disseminated infection operates primarily as a repressor and governs cell surface remodeling.

Virulence traits are often controlled by transcription regulators, i.e. sequence-specific DNA-binding proteins. The regulators that sustain microbial proliferation in the host typically work by promoting the expression of the genes that mediate such traits. Here, we report a singular example in the human fungal pathogen Candida albicans in which a transcription regulator functions by repressing the expression of virulence genes, yet its overall role is to promote virulence. We explain this apparent paradox by establishing that a major function of this protein, Zcf21p, is to set a default state of low expression of multiple cell wall components which include virulence determinants. These components comprise GPI-anchored proteins, adhesins and enzymes that synthesize cell wall sugar decorations. Deletion or overexpression of ZCF21 results in cell wall structure modifications that influence recognition and elimination of the fungus by macrophages. By leveling off the expression of adhesins, ZCF21 also prevents C. albicans self-aggregation. Balancing the expression of cell wall components - virulence determinants included - is, therefore, critical for C. albicans to assemble a cell surface configuration that is suitable to colonize mammalian tissues and evade immune surveillance.