The Role of the Endoplasmic Reticulum in Peroxisome Biogenesis

Abstract

Peroxisomes are essential cellular organelles involved in lipid metabolism. Patients affected by severe peroxisome biogenesis disorders rarely survive their first year. Genetic screens in several model organisms have identified more than 30 PEX genes that are required for the formation of functional peroxisomes. Despite significant work on the PEX genes, the biogenic origin of peroxisomes remains controversial. For at least two decades, the prevailing model postulated that peroxisomes propagate by growth and fission of preexisting peroxisomes. In this review, we focus on the recent evidence supporting a new, semiautonomous model of peroxisomal biogenesis. According to this model, peroxisomal membrane proteins (PMPs) traffic from the endoplasmic reticulum (ER) to the peroxisome by a vesicular budding, targeting, and fusion process while peroxisomal matrix proteins are imported into the organelle by an autonomous, posttranslational mechanism. We highlight the contradictory conclusions reached to answer the question of how PMPs are inserted into the ER. We then review what we know and what still remains to be elucidated about the mechanism of PMP exit from the ER and the contribution of preperoxisomal vesicles to mature peroxisomes. Finally, we discuss discrepancies in our understanding of de novo peroxisome biogenesis in wild-type cells. We anticipate that resolving these key issues will lead to a more complete picture of peroxisome biogenesis.

Pex35 is a regulator of peroxisome abundance

“…In addition, the COPI inhibitor, brefeldin A, does not inhibit peroxisome biogenesis (South et al, 2000;Voorn-Brouwer et al, 2001). However, today there is new evidence for the involvement of membrane coats in peroxisome function (David et al, 2013;Dimitrov et al, 2013;Lay et al, 2006) and it is becoming clear that peroxisome biogenesis may be distinct from peroxisome maintenance by fission. Moreover, as we saw in our own work, fluorescence microscopy alone may not be a sensitive enough readout for such changes, as sub-diffraction images can give more detailed information that may be easier to reconcile with genetic data.…”

Multifunctional Roles for the Protein Translocation Machinery in RNA Anchoring to the Endoplasmic Reticulum

“…In one view, a cohort-selective mRNA binding activity would provide a mechanism for coordinate biogenesis of the endomembrane system and/or "biogenesis domains" dedicated to preorganelle assembly, as has been proposed for peroxisome biogenesis (reviewed in Ref. 59). Such a model may be of particular relevance to the remarkable enrichment of lysosome-resident protein-encoding mRNAs in the Brij-resistant ER.…”

Expanding Proteostasis by Membrane Trafficking Networks

“…3A,B) is evident, for example, from the existence of compartments such as (1) the sarcoplasmic reticulum, a specialized ER subdomain that manages Ca 2þ -sensitive folding and signaling pathways in muscle (Zhao et al 2011); (2) peroxisomes that are specialized for managing oxidative stress (Lam et al 2011;Dimitrov et al 2013;Grimm et al 2012). Moreover, endosomal/lysosomal compartments generate a reduced pH environment to promote destabilization and metastability of the protein fold for recycling and/or degradation by the lysosome (Wickner 2010).…”

“…are temporally and spatially managed by the TPN (hazy red cloud icon) to form an integrated endomembrane system (multicolored, overlapping cloud icons outlined by a solid gray line). In this view, the ER forms a central, multitasking proteostasis hub that is linked to most (if not all) endomembrane trafficking pathways through the TPN-including mitochondria and peroxisomes (other; small gray cloud) (Friedman et al 2011;Westermann 2011;Grimm 2012;Dimitrov et al 2013). Boundaries between compartments are blurred (dotted lines around cloud icons) to illustrate the transient organization of the compartmentspecific mosaic of TRaCKS that define temporal and spatial role(s) in proteostasis biology.…”

“…Indeed, the flexibility of TPN-based TRaCKS suggests that the plethora of emerging "unconventional" pathways may have a common framework that simply reflects the versatility of TPN function-and, thus, may not be so unconventional. These now include, for example, the genesis of autophagic membranes from the ER (Gee et al 2011;Deretic et al 2012) and the identification of multiple unanticipated compartment linkages including ER-phagosome (Hubber and Roy 2010;Huang et al 2011), ER-mitochondrial (Friedman et al 2011;Westermann 2011), Golgi-cell surface (Golgi-bypass) (Nickel 2010; Grieve and Rabouille 2011), ER-peroxisome (Lam et al 2011;Dimitrov et al 2013), preGolgi -endosome (Saraste et al 2009), and intranuclear-cytoplasmic trafficking pathways (Montpetit and Weis 2012;Speese et al 2012). In this regard, Golgi structure/function relationships have been a particularly acute area of controversy with many models (Morre and Ovtracht 1977;Emr et al 2009;Papanikou and Glick 2009;Pfeffer 2010;Glick and Luini 2011;Mironov and Beznoussenko 2011;Munro 2011b).…”