In silico identification of microRNAs predicted to regulate N-myristoyltransferase and Methionine Aminopeptidase 2 functions in cancer and infectious diseases.

Ranjit Chauhan,David Datzkiw,Anuraag Shrivastav,Shailly Varma Shrivastav,Y-H Taguchi

doi:10.1371/journal.pone.0194612

Abstract

Protein myristoylation is a key protein modification carried out by N-Myristoyltransferase (NMT) after Methionine aminopeptidase 2 (MetAP2) removes methionine from the amino-terminus of the target protein. Protein myristoylation by NMT augments several signaling pathways involved in a myriad of cellular processes, including developmental pathways and pathways that when dysregulated lead to cancer or immune dysfunction. The emerging evidence pointing to NMT-mediated myristoylation as a major cellular regulator underscores the importance of understanding the framework of this type of signaling event. Various studies have investigated the role that myristoylation plays in signaling dysfunction by examining differential gene or protein expression between normal and diseased states, such as cancers or following HIV-1 infection, however no study exists that addresses the role of microRNAs (miRNAs) in the regulation of myristoylation. By performing a large scale bioinformatics and functional analysis of the miRNAs that target key genes involved in myristoylation (NMT1, NMT2, MetAP2), we have narrowed down a list of promising candidates for further analysis. Our condensed panel of miRNAs identifies 35 miRNAs linked to cancer, 21 miRNAs linked to developmental and immune signaling pathways, and 14 miRNAs linked to infectious disease (primarily HIV). The miRNAs panel that was analyzed revealed several NMT-targeting mRNAs (messenger RNA) that are implicated in diseases associated with NMT signaling alteration, providing a link between the realms of miRNA and myristoylation signaling. These findings verify miRNA as an additional facet of myristoylation signaling that must be considered to gain a full perspective. This study provides the groundwork for future studies concerning NMT-transcript-binding miRNAs, and will potentially lead to the development of new diagnostic/prognostic biomarkers and therapeutic targets for several important diseases.

Highlights

The onset of carcinogenesis is initiated by mutations to begin with in a normal cell that results in the loss of growth control
In addition to prediction of the nature of miRNA-mRNA relationships, our study revealed another layer of complexity and interconnectedness of miRNAs, long noncoding RNAs and target mRNAs
Our analysis revealed four NMT1/2 and Methionine aminopeptidase 2 (MetAP2) targeting miRNAs that have roles in hepatitis viral infections. miR-29a-5p is demonstrated to be upregulated in Hepatitis B Virus infection related to hepatocellular carcinoma and may function through inhibition of PTEN (131)

Summary

Introduction

The onset of carcinogenesis is initiated by mutations to begin with in a normal cell that results in the loss of growth control (hyperplasia). The culprit for driving such traits in the journey of a normal cell to cancer is primarily dysregulation of the signaling in the abnormal microenvironment in which these cancerous cells exists, which plays an important role in escaping the immune cells responsible for policing them. Of the signaling molecules implicated in either immune dysfunction or cancer, N-myristoyltransferase (NMT), the enzyme responsible for the covalent attachment of a 14C myristic fatty acid to the N-terminus of target proteins, has been shown to be implicated in both the development of cancer and impaired immune cell function [2,3,4,5,6]. The biological role of NMT serves as a promising candidate to study with regards to cancer progression and immune function as its dysregulation has been shown to contribute to defective embryo and monocyte development, cell growth, T-cell signaling, and HIV infection. Little is known about the regulation of its expression, signaling, and localization [4, 5, 8,9,10]

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Results

Conclusion