How alternative splicing affects membrane-trafficking dynamics

Abstract

The cell biology field has outstanding working knowledge of the fundamentals of membrane-trafficking pathways, which are of critical importance in health and disease. Current challenges include understanding how trafficking pathways are fine-tuned for specialized tissue functions and during development. In parallel, the ENCODE project and numerous genetic studies have revealed that alternative splicing regulates gene expression in tissues and throughout development at a post-transcriptional level. This Review summarizes recent discoveries demonstrating that alternative splicing affects tissue specialization and membrane-trafficking proteins during development, and examines how this regulation is altered in human disease. We first discuss how alternative splicing of clathrin, SNAREs and BAR-domain proteins influences endocytosis, secretion and membrane dynamics, respectively. We then focus on the role of RNA-binding proteins in the regulation of splicing of membrane-trafficking proteins in health and disease. Overall, our aim is to comprehensively summarize how trafficking is molecularly influenced by alternative splicing and identify future directions centered on its physiological relevance.

tappAS: a comprehensive computational framework for the analysis of the functional impact of differential splicing

“…DE-regulation is also the main driver of some processes related to oligodendrocyte function, such as immune response and lipid metabolism, likely related to myelination ( Figure 3D). On the contrary, preferential regulation by AltTP is present for core of terms related to vesicle transport, in line with the known role of vesicle trafficking for polarity establishment and myelination [70][71][72] , and with previous reports of splicing regulation of vesicle transport 73 , also during differentiation processes 74 . A second group of terms related to signalling and cell communication also appears highly regulated by DIU, which together suggest high importance of AltTP in the response to extracellular signals, as recently reported 75 .…”

Modulation of alternative splicing of trafficking genes by genome editing reveals functional consequences in muscle biology

“…Alternative splicing regulates numerous membrane-trafficking proteins which are involved in clathrin-mediated endocytosis, secretory pathways, and membrane dynamics (Blue et al, 2018). Alternative splicing and membrane trafficking are fundamental cellular processes; however, we do not know how splicing-trafficking networks modulate tissue identity acquisition and maintenance, or intracellular architecture.…”

“…Numerous trafficking genes are regulated by alternative splicing (Blue et al, 2018; Brinegar et al, 2017; Dillman et al, 2013; Giudice et al, 2014; Hannigan et al, 2017; Irimia et al, 2014), a post- and co-transcriptional mechanism by which single genes produce multiple transcripts and therefore multiple protein isoforms. Approximately 95% of human genes undergo alternative splicing (Pan et al, 2008; Wang et al, 2008) and coordinated splicing networks regulate organ development as well as tissue identity acquisition and maintenance (Baralle and Giudice, 2017).…”

“…Membrane trafficking controls numerous functions within the cells including cell communication during organ development, internalization of ion channels, receptors and ligands to control homeostasis and signaling, the transport of newly synthetized proteins, and the dynamics of organelles such as mitochondria, endosomes, lysosomes, among others (Blue et al, 2018). Intracellular trafficking is especially important in heart and skeletal muscle because of the large size of the cells that comprise these tissues.…”

Genome-wide identification of alternative splicing events that regulate protein transport across the secretory pathway

“…AS has been shown to react to various external stimuli in a highly dynamic manner (Heyd and Lynch, 2011;Preußner et al, 2017), and would thus be perfectly suited to control protein secretion in response to changing cellular environments. Although such a connection has been suggested, this was mainly based on in silico predictions (Blue et al, 2018). We have previously described how AS of SEC16A exon 29 increases the efficiency of the early secretory pathway (Wilhelmi et al, 2016) but this remains one isolated example.…”