Regulation of protein biosynthetic activity during growth arrest

Abstract

Heterotrophic bacteria grow and divide rapidly when resources are abundant. Yet resources are finite, and environments fluctuate, so bacteria need strategies to survive when nutrients become scarce. In fact, many bacteria spend most of their time in such conditions of nutrient limitation, and hence they need to optimise gene regulation and protein biosynthesis during growth arrest. An optimal strategy in these conditions must mitigate the challenges and risks of making new proteins, while the cell is severely limited for energy and substrates. Recently, ribosome abundance and activity were measured in these conditions, revealing very low amounts of new protein synthesis, which is nevertheless vital for survival.The underlying mechanisms are only now starting to be explored. Improving our understanding of the regulation of protein production during bacterial growth arrest could have important implications for a wide range of challenges, including the identification of new targets for antibiotic development. What are the causes of growth arrest?Many heterotrophic bacteria can grow and divide rapidly if their nutritional needs are met, but this condition is the exception, not the rule. Even in nutrient-rich environments, bacterial growth itself quickly depletes local resources and causes accumulation of waste products that inhibit further rapid growth. For example, many species form dense biofilm communities, which are held together by self-produced matrices, and which quickly become self-limiting.Experimental measurements and modelling in Pseudomonas aeruginosa biofilms suggest that at thicknesses greater than about 40-70 microns, metabolism of the biofilm cells completely depletes oxygen at the base of the biofilm, leading to near-zero growth rates [1,2].Depending on the organism and environment, other macronutrients (e.g. carbon[3], nitrogen[4], or phosphorus[5]), or micronutrients (such as iron[6]) may become limiting first, but in all cases the lack of an essential substrate for new biosynthesis causes growth to stop. Outside of biofilms, heterotrophic bacteria often exist in low-nutrient environments that cause frequent growth arrest [7]. Other environmental stresses, such as reactive oxygen species, high osmolarity, and unfavourable temperature, can suppress growth by directly inhibiting ATP and/or protein synthesis [8][9][10]. Finally, bacteria (as well as fungi, plants, and animals) have evolved a wide array of weapons that specifically target the energy conservation or biosynthetic machinery of competing bacteria in order to inhibit their growth (for example, see [11]). All of these challenges would hinder growth whether there were an adaptive response from the challenged bacteria or not, but decades of work strongly suggest that complex regulation is in place to coordinate stopping replication, repressing expression of new biosynthetic machinery, and redirecting resources toward functions needed for survival (reviewed in [12,13]). Still, many questions remain about the mechanisms that allow ongoing adjust...

Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis

“…How cytoplasmic acidification influences the here uncovered halting of protein turnover as they occur in the nuo* mutants after 30 min (Fig. 5d ), is less clear as mechanisms to downregulate protein synthesis during growth arrest are not fully understood 107 . The sudden and simultaneous stop of both protein production and degradation, as we inferred from both the sudden stop in proteome changes and the decreased translation activity (Fig.…”

Horizontal Transmission of Stress Resistance Genes Shape the Ecology of Beta- and Gamma-Proteobacteria

“…Indeed, a network of proteases has recently been shown to rescue growth arrest of P. aeruginosa ( Basta et al, 2020 ). Acquisition of tLST proteases might therefore aid recovery of widely distributed P. aeruginosa clones from this environmentally relevant physiological status ( Bergkessel, 2020 ). tLST-mediated heat resistance is enhanced by the presence of 4% NaCl but this effect is mediated by accumulation of compatible solutes rather than over-expression of tLST-encoded proteins as addition of up to 4% NaCl did not increase expression from the tLST promotor that is located 63 bps upstream of the orf1 (alternatively named dna), a Mer-like transcriptional regulator ( Figure 1 ; Pleitner et al, 2012 ; Mercer et al, 2017a ).…”

Diversity in Starvation Survival Strategies and Outcomes among Heterotrophic Proteobacteria

“…Although new protein synthesis occurs at much slower average rates during starvation compared to growth [Bergkessel, 2020], it has been shown to be required for optimal survival [Yin et al, 2019]. Replacement of damaged proteins and responding to new environmental threats or opportunities are likely important functions of this low-level new protein synthesis.…”

“…The precise roles of the major regulators of the transition to stationary phase, RpoS and DksA/(p)pp-Gpp, during protracted starvation also remain to be determined [Bergkessel et al, 2016;Yin et al, 2019]. Under carbon starvation stress, bacterial regulatory strategies must either decrease activity to the greatest extent possible to best conserve limited resources, or maintain some ongoing metabolic activity to increase responsiveness to the environment [Bergkessel, 2020]. Which strategy produces the best outcome will depend on many unpredictable factors: the length of the starvation period, stochastic threats or opportunities during starvation, and the amount of competition upon arrival of new nutrients, for example.…”