On 11 January, Dr. Yanjie Chao at the Shanghai Institute of Immunity and Infection of the Chinese Academy of Sciences and Dr. Chuan Wang from Fudan University, published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) a research paper entitled “An RNase III-processed sRNA coordinates sialic acid metabolism of Salmonella enterica during gut colonization”. This study revealed how a bacterial pathogen coordinates the N-acetylneuraminic acid (Neu5Ac) metabolism at the post-transcriptional level via a novel small noncoding RNA to promote infection in the host intestinal environments.

Sialic acids are a family of alpha-keto acid sugars with a nine-carbon backbone, serving as terminal sugars on glycoproteins of cell surfaces and glycan receptors for cellular recognition. One of the most prevalent forms of sialic acids is N-acetylneuraminic acid (Neu5Ac), which serves as a receptor for some viruses like influenza or as energy source for enteropathogenic bacteria such as Salmonella enterica. The metabolism of Neu5Ac produces various amino sugar derivatives such as N-acetylglucosamine (GluNAc) and N-acetylmannosamine (ManNAc), which are then used as building blocks for the synthesis of important glycan macromolecules, such as bacterial cell wall or capsular polysaccharides. 

In order to use these amino sugar derivatives, bacteria have evolved a variety of metabolic operons that encode specific glycan transporters and enzymes. However, how bacteria synergize these different systems during sialic acid metabolism to adapt to the host intestinal environment is poorly understood.

The researchers identified a unique genomic island in pathogenic Salmonella containing five proteins of unknown function and a small noncoding RNA, using a comparative genomics approach. Through AlphaFold structure prediction, combined with gene knockout, gene expression assays, transcriptional activity test, metabolism and growth analysis, the researchers discovered that this five-gene island is responsible for metabolizing Neu5Ac, and that its encoded genes are directly activated by ManNAc, the initial degradation product of Neu5Ac catabolism. 

Further analysis of the genes transcribed from the genomic island revealed that the 3’UTR of mRNA was processed to generate ManS, a novel small noncoding RNA of 80 nt in length. Importantly, ManS was produced by a noncanonical biogenesis mechanism: the ribonuclease RNase III, which usually cut double-stranded RNA, cleaves at a single-stranded region in the mRNA 3’UTR, resulting in the production of ManS sRNA with multiple isoforms of varying sizes. 

                                     Fig. Model depicting the function of ManS in balancing ManNAc metabolism. (Image by SIII)

Functional studies revealed that ManS isoforms with a single seed region directly regulate Neu5Ac/ManNAc metabolism by repressing the GlcNAc phosphotransferase system (PTS) permease NagE. In contrast, isoforms with dual seed regions regulate multiple genes involved in central and secondary metabolic pathways, specifically linked to ManNAc metabolism. This intricate regulatory mechanism significantly influences global transcriptomic, proteomic, and metabolomic profiles in vitro, as well as the competitive fitness of S. enterica during gut infection in vivo.

In summary, the present study not only discovered a novel 3′ UTR-derived sRNA but also expanded the understanding of RNase III-mediated RNA processing. Furthermore, it highlights the critical role of ManNAc in bacterial adaptation within host environments, offering new insights into the molecular mechanisms underpinning Salmonella pathogenesis.

Link of CAS: https://english.cas.cn/newsroom/research_news/life/202501/t20250113_898333.shtml