Exploring m6A-RNA methylation as a potential therapeutic strategy for acute lung injury and acute respiratory distress syndrome

Abstract

N⁶-methyladenosine (m6A) is the most common methylation modification in mammalian messenger RNA (mRNA) and noncoding RNAs. m6A modification plays a role in the regulation of gene expression and deregulation of m6A methylation has been implicated in many human diseases. Recent publications suggest that exploitation of this methylation process may possess utility against acute lung injury (ALI). ALI and its more severe form, acute respiratory distress syndrome (ARDS) are acute, inflammatory clinical syndromes characterized by poor oxygenation and diffuse pulmonary infiltrates. This syndrome is associated with microvascular endothelial dysfunction, subsequent pulmonary hypertension and may ultimately lead to mortality without rigorous and acute clinical intervention. Over the years, many attempts have been made to detect novel therapeutic avenues for research without much success. The urgency for the discovery of novel therapeutic agents has become more pronounced recently given the current pandemic infection of coronavirus disease 2019 (COVID-2019), still ongoing at the time that this review is being written. We review the current landscape of literature regarding ALI and ARDS etiology, pathophysiology, and therapeutics and present a potential role of m6A methylation. Additionally, we will establish the axiomatic principles of m6A methylation to provide a framework. In conclusion, METTL3, or methyltransferase-like 3, the selective RNA methyltransferase for m6A, is a hub of proinflammatory gene expression regulation in ALI, and using a modern drug discovery strategy will identify new and effective ALI drug candidates targeting METTTL3.

Keywords: Acute Respiratory Distress Syndrome; acute lung injury; m6A‐RNA methylation.

Figure 1

(a) METTL3‐METTL14 complex. ~200 kDa Methyltransferase complex (70 kDa METTL3). METTL3 and METTL14 form a heterodimeric methyltransferase complex within the nuclear RNA that catalyzes RNA methylation. (b) METTL3‐METTL14 complex bound to S‐adenosyl methionine (SAM). METTL3 is the catalytically active subunit with a binding pocket for SAM and METTL14 functions as the structural component of the complex that facilitates substrate recognition.

Figure 2

m6A modification mechanism (the life cycle of m6A RNA). m6A modification is facilitated by the “writer” complex consisting of methyltransferase 3 (METTL3), methyltransferase 14 (METTL14), and Wilms Tumor1‐associated protein (WTAP) that make up the core along with regulatory cofactors (not pictured here). METTL3 acts as the core subunit that binds to S‐adenosylmethionine (SAM) and catalyzes the transfer of a methyl group. METTL14 is an RNA‐binding supportive unit that binds to METTL3 and WTAP allows for localization of the METTL3‐METTL14 heterodimer to the nuclear speckle. m6A is a reversible modification as demethylase proteins alkB homolog 5 RNA demethylase (ALKBH5) and alpha‐ketoglutarate‐dependent dioxygenase (FTO), also known as erasers, remove methyl groups from the N6 position of adenine. m6A modifications are recognized by “reader” elements that ultimately decide the fate of the modified mRNA. A wide range of readers have been discovered and characterized. A few examples of readers and their functions are presented above. YTHDC1, HNRNPA2B1, and HNRNPC promote RNA splicing while YTHDF2/3 and YTHDC2 accelerate RNA decay, and so forth. m6A, N⁶‐methyladenosine; mRNA, messenger RNA.

Figure 3

Role of METTL3 and METTL14‐mediated m6A methylation in human pathology. METTL3 and METTL14 act as m6A regulators that can affect the progression of different human pathologies through oncogenic or suppressive methods. In several human cancers, for example, METTL3 plays an oncogenic role by upregulating oncogenes that support tumor progression. Conversely, METTL3 also behaves as a suppressor in the central nervous system (CNS) by upregulating tumor suppressor genes as well as genes that promote synaptic damage. METTL14 may enhance the growth and metastasis of pancreatic cancer through decreased expression of a vital oncogene through m6A modification. m6A, N⁶‐methyladenosine.