Metabolic regulation via enzyme filamentation

Figures & data

Figure 1. Cytoophidia exist in various organisms. CTPS has been found forming filamentous structures in fruit flies (Liu, 2010), bacteria (Ingerson-Mahar et al., 2010), budding yeast (Noree et al., 2010), fission yeast (Zhang et al., 2014) and human cells (Carcamo et al., 2011; Chen et al., 2011). (A) In the fruit fly (Drosophila melanogaster) follicle cells, overexpressing CTPS-GFP (green) leads to long cytoophidia. (B) Cytoophidia, labeled by CTPS-GFP (green), is detectable in budding yeast (Saccharomyces cerevisiae). (C) Cytoophidia, labeled by CTPS-GFP (green), is detectable in fission yeast (Schizosaccharomyces pombe). (D) CTPS1-GFP (green) and IMPDH (red) form filamentous cytoophidia in human (Homo sapiens) HEK293T cells. Image in D is kindly provided by Chia Chun Chang and Li-Ying Sung from National Taiwan University. Nuclei are labeled by DNA dyes (magenta in A–C; blue in D). Scale bars, 10 μm. (see colour version of this figure at www.informahealthcare.com/bmg)

Figure 2. Schematic representation of proposed mechanisms of CTPS polymer assembly. (A) Mechanism demonstrated by Barry et al. (2014). Active CTPS tetramers (left) undergo conformational change dependant on CTP concentration leading to polymer formation of interdigitated tetramer subunits. Multiple polymers associate into cytoplasmic filaments (right). (B) Mechanism proposed by Aughey et al. (2014) and Noree et al. (2014). Polymerization is dependent on dimerization/tetramerization state of CTPS. Catalytically active tetramers (left) dissociate into constituent dimers for inclusion into inactive cytoplasmic filaments (right). Both mechanisms rely on increasing CTP concentration to promote filament assembly (increasing left to right). (see colour version of this figure at www.informahealthcare.com/bmg)

Figure 3. Schematic demonstrating hypothesized cellular functions of cytoophidia beyond regulation of enzymatic activity. (A) “Storage depot” downregulation or “Activator” upregulation of enzyme activity by filament assembly, as demonstrated by (Aughey et al., 2014; Barry et al., 2014; Noree et al., 2014) and (Chang et al., 2015; Strochlic et al., 2014), respectively. (B) Filament formation mediates structural roles analogous to cytoskeletal filaments as demonstrated in C. crescentus (Ingerson-Mahar et al., 2010). (C) The cytoophidium provides an intracellular scaffold for the sequestration of further cytoplasmic proteins. (D) Formation of intracellular filaments regulates traffic of CTPS between cellular compartments. (see colour version of this figure at www.informahealthcare.com/bmg)

Table 1. Filament-forming proteins and their regulators^a.

Protein	Effect of filament formation on catalytic activity	Induced by	Dissociated by	References
Acetyl-CoA carboxylase (ACC)	Enhanced	Citrate, MIG12	Malonyl-CoA	(Beaty & Lane, 1983a,b; Kim et al., 2010; Kleinschmidt et al., 1969)
Glutamate dehydrogenase (GDH)	Unknown	ADP	GTP, NADH	(Zeiri & Reisler, 1978)
Glutamate synthase	Unknown	Unknown	Unknown	(Noree et al., 2014)
Glutamine synthase	Unknown	Zinc, nutrient restriction	Unknown	(Miller et al., 1974, Petrovska et al., 2014)
GDP-mannose pyrophosphorylase	Unknown	Unknown	Unknown	(Noree et al., 2014)
Mps1/Polo	Unknown	Hypoxia	Collagenase	(Gilliland et al., 2009)
UDP-N-acetylmuramate-alanine ligase	Unknown	Unknown	Unknown	(Werner et al., 2009)
IRE1	Enhanced	Stress response	Unknown	(Korennykh et al., 2009; Li et al., 2010)
Cytidine-5’-triphosphate synthase (CTPS)	Reduced	CTP, Glutamine analogs, nutrient restriction	Unknown	(Ingerson-Mahar et al., 2010; Liu, 2010; Noree et al., 2010)
Inosine-5’-monophosphate dehydrogenase (IMPDH)	Enhanced	Mycophenolate, Ribavirin	Unknown	(Chang et al., 2015; Gunter et al., 2007; Ji et al., 2006)
Nitrilase	Unknown	Unknown	Unknown	(Thuku et al., 2007)
Β-glucosidase	Enhanced	Unknown	Unknown	(Gunning, 1965, Kim et al., 2005)
Activated Cdc42 kinase (dAck)	Unknown	Unknown	Unknown	(Strochlic et al., 2014)

^aNovel filament-forming proteins recently identified in Shen et al., 2016 are not included in this table.

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