Dual targeting of peroxisomal proteins

Abstract

Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed.

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

“…Generally, peroxisomes are known to be highly variable in size, shape, number and protein content (Fransen 2012); nevertheless, to the best of our knowledge, a significant decrease in peroxisomal size after drug administration was not reported so far for mammalian cells. Interestingly, it is reported that peroxisomal proteins can be differentially localized within the cell depending on differential splicing, multiple targeting signals or phosphorylation (Fordor et al 2012;Ast et al 2013). However, dual localization of peroxisomal proteins was predominantly reported to occur into the cytosol and into mitochondria (Ast et al 2013), merely one study in yeast described nuclear translocation of a peroxisomal NAD + -dependent glycerol 3-phosphate dehydrogenase (Jung et al 2010).…”

“…Interestingly, it is reported that peroxisomal proteins can be differentially localized within the cell depending on differential splicing, multiple targeting signals or phosphorylation (Fordor et al 2012;Ast et al 2013). However, dual localization of peroxisomal proteins was predominantly reported to occur into the cytosol and into mitochondria (Ast et al 2013), merely one study in yeast described nuclear translocation of a peroxisomal NAD + -dependent glycerol 3-phosphate dehydrogenase (Jung et al 2010). The concurrent analysis of the intracellular distribution of catalase, another peroxisomal protein, demonstrated a comparable propiverine-mediated mislocalization from the peroxisomes to the cytosol and nucleus, thereby suggesting the presence of more generalized compound-mediated reduced or abrogated translocation to or import of peroxisomal proteins into peroxisomes.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…However, more recently, the number of reports describing real bilocalization of individual proteins by dual targeting has been steadily increasing, which has been summarized for proteins localized in peroxisomes and other organelles (Ast et al, 2013), mitochondria and chloroplasts (Small et al, 1998;Carrie and Small, 2013), or secretory proteins and other organelles (Porter et al, 2015). These observations were sometimes made by accident, but more often were facilitated by modern techniques such as the detailed analysis of subcellular fractionation by advanced mass spectrometric methods (e.g., protein correlation profiling), which allows a better discrimination of organellar constituents from contaminants (Andersen and Mann, 2006;Foster et al, 2006;Wiese et al, 2007), or by the systematic investigation of EGFP-fusion proteins (Li et al, 2006;Carrie et al, 2009).…”

“…Protein variants that encode targeting signals at the opposite ends of the protein probably necessitate the omission of the N-terminal targeting signal to disclose a functional PTS1 (lower panel). Thus, the two protein variants should differ in the absence or presence of the N-terminal targeting signal, which can be achieved by the omission of the N-terminal part of the protein sequence either by alternative translation initiation or leaky ribosome scanning (Elgersma et al, 1995;Wamboldt et al, 2009), next to the abovementioned mechanisms of alternative splicing and alternative transcription initiation (Ast et al, 2013).…”

Origin and spatiotemporal dynamics of the peroxisomal endomembrane system

“…They discuss the recent advances in our understanding of the mechanisms underlying the formation of a receptor/cargo-complex in the cytosol and its subsequent docking at the peroxisomal membrane, the translocation of the cargo protein across the membrane and its release into the peroxisomal matrix, and the recycling of receptor molecules. Ast et al (2013) discuss the molecular mechanisms by which isoforms of proteins known to be peroxisomal can also be actively sorted to the cytosol, mitochondrion, nucleus, or plastid. The authors hypothesize that such dual sorting of peroxisomal proteins within a cell could have an important role in extending the metabolic capacity of peroxisomes in response to specific changes in cell physiology and/or environmental conditions.…”