Nutrient availability as an arbiter of cell size

Abstract

Pioneering work carried out over 60 years ago discovered that bacterial cell size is proportional to the growth rate set by nutrient availability. This relationship is traditionally referred to as the 'growth law'. Subsequent studies revealed the growth law to hold across all orders of life, a remarkable degree of conservation. However, recent work suggests the relationship between growth rate, nutrients, and cell size is far more complicated and less deterministic than originally thought. Focusing on bacteria and yeast, here we review efforts to understand the molecular mechanisms underlying the relationship between growth rate and cell size.

Keywords: cell cycle; cell growth; cell size; metabolism; nutrients.

Figure 1.. Nutrients modulate microbial size through changes in cell growth and cell cycle progression.

A) Bacterial cell size increases exponentially with increases in nutrient-imposed growth rate B) In yeast and bacteria, signals from biosynthesis modulate the amount of growth required for cell cycle progression. Nutrients directly impact biosynthesis which in turn impacts cell growth and multiple aspects of cell cycle progression (e.g. DNA replication, synthesis of proteins required for DNA replication and division). The ball and stick linking Biosynthesis and Cell cycle progression represents signaling pathways coupling specific metabolic pathways (e.g. UDP glucose synthesis) with specific cell cycle events (e.g. assembly of the cell division machinery) through activation of modulatory proteins.

Figure 2.. Sizer and adder models for cell size control.

A) In a sizer model, cells actively measure a parameter directly related to cell size, such as volume, length, or surface area, and use that information to trigger division. B) In adder models, cells add a constant amount of material (blue) during each cell cycle, regardless of the cell’s starting size. Over time, stochastic variations in cell size are mitigated. The line indicates the position of the division septum. Nutrients positively impact the size of adder. C) Nutrient downshift experiments in fission yeast suggest the presence of a nutrient-dependent size threshold. Cells above the threshold size for cell division in the new nutrient poor conditions immediately undergo cell division, while smaller cells delay division only until they achieve the new threshold size.

Figure 3.. Threshold model for division adder in bacteria.

Division is triggered when FtsZ molecules reach threshold numbers at the nascent septum. This threshold system ensures that cells add the same volume of material in each generation. In E. coli and B. subtilis, FtsZ accumulates in a growth dependent manner such that concentration remains constant throughout the cell cycle. The absolute concentration of FtsZ is the same across nutrient conditions supporting mass doubling times of 80 minutes or less. Left: In nutrient poor conditions all FtsZ molecules are “active” and competent for assembly at the division septum resulting in a high effective concentration (rectangle). Bacteria accumulate threshold numbers of FtsZ molecules at a relatively short cell length (triangle). Right: In nutrient rich conditions, nutrient-sensitive inhibitors interact with FtsZ to substantially reduce the effective concentration (rectangle). Blue = active FtsZ. Yellow = inactive FtsZ. Under these conditions, bacteria accumulate threshold numbers of FtsZ at a substantially longer length. Note that FtsZ is used as the example, but any essential division protein that is limiting for division could underlie adder.

Figure 4.. Master regulators coordinate biosynthesis to modulate cell growth and size.

Left: In bacteria, guanosine tetraphosphate (ppGpp) is responsible for the homeostatic regulation of biosynthetic capacity in response to changes in nutrient availability and other stressors. Nutrients impact the synthesis and/or accumulation of ppGpp via changes in the activity of synthases and hydrolases (RelA and SpoT respectively in E. coli). ppGpp accumulation ensures that a slowdown in one pathway in response to limitation of a specific nutrient (e.g. nitrogen) triggers similar reductions in other areas of biosynthesis (e.g. fatty acid synthesis). ppGpp directly regulates DNA synthesis, transcription, and translation and has direct and indirect effects on fatty acid synthesis. ppGpp-mediated inhibition of fatty acid synthesis reduce cell size by limiting the capacity of the bacterial cell envelope. Right: In yeast, TOR signaling plays a crucial role in the mechanisms by which nutrients modulate cell size and growth rate. The schematic provides a simplified overview that only includes components of the network that are known to influence nutrient modulation of cell size and growth rate.