Protein N-myristoylation is a cotranslational lipidic modification specific to the alpha-amino group of an N-terminal glycine residue of many eukaryotic and viral proteins. The ubiquitous eukaryotic enzyme, N-myristoyltransferase, catalyzes the myristoylation process. Precisely, attachment of a myristoyl group increases specific protein–protein interactions leading to subcellular localization of myristoylated proteins with its signaling partners. The birth of the field of myristoylation, a little over three decades ago, has led to the understanding of the significance of protein myristoylation in regulating cellular signaling pathways in several biological processes especially in carcinogenesis and more recently immune function. This review discusses myristoylation as a prerequisite step in initiating many immune cell signaling cascades. In particular, we discuss the hitherto unappreciated implication of myristoylation during myelopoiesis, innate immune response, lymphopoiesis for T cells, and the formation of the immunological synapse. Furthermore, we discuss the role of myristoylation in inducing the virological synapse during human immunodeficiency virus infection as well as its clinical implication. This review aims to summarize existing knowledge in the field and to highlight gaps in our understanding of the role of myristoylation in immune function so as to further investigate into the dynamics of myristoylation-dependent immune regulation.

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N-Myristoyltransferase (NMT) transfers myristate to an amino-terminal glycine of many eukaryotic proteins. In yeast, worms, and flies, this enzyme is essential for viability of the organism. Humans and mice possess two distinct but structurally similar enzymes, NMT1 and NMT2. These two enzymes have similar peptide specificities, but no one has examined the functional importance of the enzymes in vivo. To address this issue, we performed both genetic and biochemical studies. Northern blots with RNA from adult mice and in situ hybridization studies of day 13.5 embryos revealed widespread expression of both Nmt1 and Nmt2. To determine whether the two enzymes are functionally redundant, we generated Nmt1-deficient mice carrying a ␤-galactosidase marker gene. ␤-Galactosidase staining of tissues from heterozygous Nmt1-deficient (Nmt1؉/؊) mice and embryos confirmed widespread expression of Nmt1. Intercrosses of Nmt1؉/؊ mice yielded no viable homozygotes (Nmt1؊/؊), and heterozygotes were born at a less than predicted frequency. Nmt1؊/؊ embryos died between embryonic days 3.5 and 7.5. Northern blots revealed lower levels of Nmt2 expression in early development than at later time points, a potential explanation for the demise of Nmt1؊/؊ embryos. To explore this concept, we generated Nmt1؊/؊ embryonic stem (ES) cells. The Nmt2 mRNA could be detected in Nmt1؊/؊ ES cells, but the total NMT activity levels were reduced by ϳ95%, suggesting that Nmt2 contributes little to total enzyme activity levels in these early embryo cells. The Nmt1؊/؊ ES cells were functionally abnormal; they yielded small embryoid bodies in in vitro differentiation experiments and did not contribute normally to organogenesis in chimeric mice. We conclude that Nmt1 is not essential for the viability of mammalian cells but is required for development, likely because it is the principal N-myristoyltransferase in early embryogenesis.