life Review Post-Transcriptional Control in the Regulation of Polyhydroxyalkanoates Synthesis Alexandra Peregrina 1,* , João Martins-Lourenço 1, Filomena Freitas 2,3 , Maria A. M. Reis 2,3 and Cecília M. Arraiano 1,* 1 Control of Gene Expression Lab., Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal; [email protected] 2 Associate Laboratory i4HB-Institute for Health and Bioeconomy, School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal; [email protected] (F.F.); [email protected] (M.A.M.R.) 3 UCIBIO—Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal * Correspondence: [email protected] (A.P.); [email protected] (C.M.A.) Abstract: The large production of non-degradable petrol-based plastics has become a major global issue due to its environmental pollution. Biopolymers produced by microorganisms such as polyhy- droxyalkanoates (PHAs) are gaining potential as a sustainable alternative, but the high cost associated with their industrial production has been a limiting factor. Post-transcriptional regulation is a key step to control gene expression in changing environments and has been reported to play a major role in numerous cellular processes. However, limited reports are available concerning the regulation of PHA accumulation in bacteria, and many essential regulatory factors still need to be identified. Here, we review studies where the synthesis of PHA has been reported to be regulated at the post- transcriptional level, and we analyze the RNA-mediated networks involved. Finally, we discuss the Citation: Peregrina, A.; forthcoming research on riboregulation, synthetic, and metabolic engineering which could lead to Martins-Lourenço, J.; Freitas, F.; Reis, M.A.M.; Arraiano, C.M. improved strategies for PHAs synthesis in industrial production, thereby reducing the costs currently Post-Transcriptional Control in the associated with this procedure. Regulation of Polyhydroxyalkanoates Synthesis. Life 2021, 11, 853. https:// Keywords: polyhydroxyalkanoates; mcl-PHA; scl-PHA; post-transcriptional regulation; riboregulation; doi.org/10.3390/life11080853 small non-coding RNAs Academic Editor: Stéphane D. Lemaire 1. Introduction Received: 30 July 2021 1.1. The Age of Plastics Accepted: 18 August 2021 Petroleum-based plastics are pervasively used and appear as cheap and easy to make Published: 20 August 2021 but at the cost of the environmental toll [1,2]. Eight million tons of plastic end up in the oceans every year, where they break down into micro-and nanoplastics [3,4]. Plastics have Publisher’s Note: MDPI stays neutral also been found falling out of the air in several mountain locations. This discovery suggests with regard to jurisdictional claims in that, after the evaporation of the water, microplastics are carried around the planet in published maps and institutional affil- iations. atmospheric winds, becoming part of the breathable air [5]. The impact of deposition of waste plastics in the land is also extremely relevant. Animals eat plastic and can get wrapped up, trapped, or asphyxiated by them [6]. In addition, plastics can easily enter the food chain and have adverse consequences for humans. During their processing and consumption, they release toxic additives that were used to shape them, harden them, or Copyright: © 2021 by the authors. make them flexible, and these additives can enter into the food chain and water supply. Licensee MDPI, Basel, Switzerland. For instance, bisphenol A (BPA), a common precursor of widely used plastics, was found This article is an open access article in the urine of approx. 93% of the 2517 individuals tested in a study [7]. In addition, distributed under the terms and conditions of the Creative Commons these molecules could interfere with our endocrine system since they are thought to adopt Attribution (CC BY) license (https:// hormonal functions in the human body [8]. creativecommons.org/licenses/by/ Therefore, to break the plastic wave, bio-based and biodegradable alternatives to 4.0/). synthetic plastics should be considered [9,10], especially with the drastic increase in plastic Life 2021, 11, 853. https://doi.org/10.3390/life11080853 https://www.mdpi.com/journal/life Life 2021Life 2021, 11,, 85311, x FOR PEER REVIEW 2 of 20 2 of 19 pollutionTherefore, due to break the current the plastic COVID-19 wave, bio-based pandemic and [ 11biodegradable,12]. However, alternatives the elevated to cost ofsynthetic industrial plastics procedures should be cons andidered lack of [9,10], significant especially large-scale with the drastic production increase[ in13 plastic–16], together pollution due to the current COVID-19 pandemic [11,12]. However, the elevated cost of with the availability of appropriated carbon sources, have limited faster progress in these industrial procedures and lack of significant large-scale production [13–16], together with processes and consequently greater market penetration [17,18]. the availability of appropriated carbon sources, have limited faster progress in these processes and consequently greater market penetration [17,18]. 1.2. Polyhydroxyalkanoates: Bio-Based Biodegradable Plastics 1.2. Polyhydroxyalkanoates:The word “bioplastics” Bio-Based has Biodegradable commonly Plastics been used to make a distinction from petro- chemicalThe word polymers, “bioplastics” which ishas partially commonly misleading, been used since to make not alla typesdistinction of bioplastics from are bio-basedpetrochemical and polymers, biodegradable which is [16 partially,19] (Figure misleading,1A). Some since bioplastics not all types are of biodegradable bioplastics but fullyare bio-based fossil-based. and biodegradable Their chemical [16,19] structure (Figure can1A). beSome degraded bioplastics in aare slow biodegradable process catalyzed bybut enzymes fully fossil-based. of some aerobicTheir chemical and anaerobic structure microorganisms can be degraded that in are a widelyslow process distributed in variouscatalyzed ecosystems. by enzymes However, of some aerobic they are and not anaerobic biodegradable microorganisms in animal that bodies are andwidely sometimes theydistributed remain in various in marine ecosystems. waters However, [16,20] (Figure they are1A, not bottom-right). biodegradable in Others animal arebodies bio-based butand chemicallysometimes they identical remain to in their marine fossil waters counterparts, [16,20] (Figure so 1A, they bottom-right). are not biodegradable Others are [16,21] (Figurebio-based1A, but upper-left). chemically identical to their fossil counterparts, so they are not biodegradable [16,21] (Figure 1A, upper-left). Only bio-based and biodegradable bioplastics are more ecologically friendly and serve Only bio-based and biodegradable bioplastics are more ecologically friendly and as the best substitute for conventional plastics (Figure1A, upper-right). Among them, one serve as the best substitute for conventional plastics (Figure 1A, upper-right). Among ofthem, the mostone of promising the most classpromising of bioplastics class of arebioplastics the bacterial are the polyesters bacterial polyhydroxyalka-polyesters noatespolyhydroxyalkanoates (PHAs), which are(PHAs), produced which through are produced industrial through bacterial industrial fermentation bacterial of sugar or lipidsfermentation by numerous of sugar Gram-positiveor lipids by numerous and Gram-negative Gram-positive and bacteria Gram-negative [16,20]. Insidebacteria the cells, PHAs[16,20]. moleculesInside the cells, aggregate PHAs molecules to form water-insoluble aggregate to form granules, water-insoluble the carbonosomes, granules, the which arecarbonosomes, intracellular which reserves are intracellular of energy reserves during starvationof energy during [22,23 starvation] (Figure1 [22,23]B). In (Figure carbonosomes there1B). In is carbonosomes a constant cycle there of is synthesis a constant and cycle degradation, of synthesis and and thisdegradation, bidirectional and this process is a greatbidirectional advantage process in the is adaptationa great advantage to rapid in changes the adaptation in the environmentto rapid changes [24,25 in]. the During the lastenvironment few years, [24,25]. PHAs During are being the last proclaimed few years, asPHAs the are best being alternative proclaimed to fossil-based as the best plastic duealternative to their to goodfossil-based balance plastic between due to biodegradabilitytheir good balance between rate, material biodegradability properties rate, that range frommaterial thermoplastics properties that to range elastomers, from thermoplastics and the possibility to elastomers, to be and processed the possibility into different to be final processed into different final products [9,10,26]. However, production costs of PHAs are products [9,10,26]. However, production costs of PHAs are still too high when compared still too high when compared to the synthetic plastics [13,14]. Although they have not yet toreached the synthetic industrial plastics scale, in [13 the,14 ].last Although decade a theymore havecost-effective not yet reachedprocesses industrialfor the scale, inproduction the last decadeof PHA have a more been cost-effective developed based processes on the use for of the wastes, production industrial of products PHA have been developedand less energy-demanding based on the use approaches of wastes, [27,28] industrial. Once the