Abstract
Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, but when dysregulation in splicing occurs this can have important impact on health and disease. Alternative splicing is widely used in the mammalian immune system to control the development and function of antigen specific lymphocytes. In this review we will examine the splicing of pre-mRNAs yielding key proteins in the immune system that regulate apoptosis, lymphocyte differentiation, activation and homeostasis, and discuss how defects in splicing can contribute to diseases. We will describe how disruption to trans-acting factors, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), can impact on cell survival and differentiation in the immune system.
Highlights
The immune system has evolved to respond to a myriad of pathogens
Recent studies by Butte et al [113], identified that T cell activation via T cell receptor (TCR) and CD28 signaling leads to increased splicing of a wide range of target genes. They found a range of target genes, some of which were known to be controlled by hnRNPLL [63] that underwent alternative splicing in response to TCR/CD28 signaling compared to TCR signaling alone [113]
Consistent with its function in IgD production, mRNA levels of Zfp318 in IgD+ B cells is higher compared to other IgDsubsets [142,143,144]. These findings suggest the Ighd splicing is promoted during the maturation of B cells into IgD-expressing cells and this process is controlled by ZFP318 [142,143]
Summary
The immune system has evolved to respond to a myriad of pathogens. It is composed of two effector arms known as the innate and adaptive immune systems and they have specialized roles to play in protecting the host from infectious diseases and maintaining long-term health [1,2]. The innate immune system is composed of physical barriers such as the skin and mucous membranes but it is composed of specialized cells such as macrophages, dendritic cells and granulocytes including neutrophils, basophils and mast cells Many of these cells have a phagocytic function to help remove cellular debris and pathogens to maintain tissue homeostasis. These innate immune cells play a critical role to trigger adaptive immune responses [1,2]. We will examine the role of specific heterogeneous nuclear ribonucleoproteins (hnRNPs) in the regulation of pre-mRNA alternative splicing to illustrate how these proteins can impact on immune cell development and function
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