Extracellular RNAs are identified as a new type of signalling molecules: RNAkines

    Throughout the history of RNA research, one can immediately notice a significant breakthrough during 2007 and 2008, in which several groups independently reported the discovery of intact noncoding RNA (ncRNA) sequences in extracellular space. Later on, the discovery of these extracellular ncRNAs leads to a scope switch of RNA study, from their regulatory roles within the cells to signalling properties in cell-to-cell communications. Extracellular ncRNAs travel in extracellular space by either associating with extracellular vesicles (EVs) or proteins. Zhang et al. first reported the signalling property of extracellular miRNAs by showing how monocyte-secreted miRNAs via EVs are taken up by recipient endothelial cells, in which they act like endogenous miRNAs regulating angiogenesis. Since then, evidence increasingly mounts on the significant roles of extracellular miRNAs in various physiological and pathological processes. More importantly, the secretion of extracellular ncRNAs is proved to be a highly regulated process and specifically responds to various types of physiological or pathological stimuli. Therefore, extracellular ncRNAs are progressively considered a novel type of molecules that signal homeostatic changes between origin and recipient cells.

    Despite the growing recognition of unique functional characteristics and relevance of extracellular ncRNAs, there remains a lack of universally accepted terminology for unequivocally identifying these molecules. The proposed terms, such as EV-RNAs and secreted RNAs, albeit have their merits, fall short of capturing their significance and characteristic as bona fide factors of intercellular communications, adding complexity and uncertainty to their understanding.

    In a recent publication in Trends in Endocrinology & Metabolism, the research team of Prof. Chen-Yu Zhang (Nanjing University), Prof. Antonio Vidal-Puig (University of Cambridge) and Dr. Jing Li (Nanjing University) introduces a new nomenclature “RNAkine” for naming extracellular ncRNAs. Leveraging the suffix “-kine”, which originally means movement and action, this unified and distinctive nomenclature vividly reflects the properties of extracellular ncRNAs as regulators in a diverse range of essential biological processes.

    They state that the rationale behind coining this new term first lies in the shared biological roles with conventional signalling molecules for their actively regulated release and signalling capability. More importantly, extracellular ncRNAs cannot be simply included into the category of conventional signalling molecules, since they differ from conventional signalling molecules in many aspects. New nomenclature helps set up a unique self-contained category, which can encompass all nucleic acids functioning in intercellular communications, such as circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs). In addition, extracellular ncRNAs signal recipient cells in a different way. They act as endogenous ncRNAs, simultaneously targeting different components of biological networks, leading to coordinated and integrated responses. More importantly, the term “RNAkine” emphasises their different but co-dependent roles with conventional signalling molecules in contributing to specific physiological processes or disease. The current evidence strongly indicates that RNAkines and conventional signalling molecules operate in concert but also hierarchically. Conventional signalling molecules often work for the central control of the whole-body homeostasis. For examples, leptin adjusts food intake and energy stores in response to overall energy balance of the body. During tumorigenesis, host-derived cytokines can orchestrate immune system to suppress tumour formation. In contrast, RNAkines typically work for supporting functionality of local tissues. A typical example is that brown adipose tissue (BAT) sends RNAkines to recruit fuel for thermogenesis in response to cold challenge. The nuanced hierarchical roles of conventional signalling molecules and RNAkines should be studied further, and the term “RNAkine” can help indicate their different regulatory scale in a certain biological process.

    In summary, extracellular RNAs that are actively released and have signalling capabilities in cell-to-cell communications can be identified as RNAkines. This nomenclature not only provides a precise definition of extracellular RNAs, but also fosters consensus and holds the potential for the wide spread acceptance within the scientific and clinical communities.